16alpha, 17alpha-methylene-6-substituted progesterones and process therefor



United States Patent 0 3,086,029 160a,17ot-METHYLENE-6-SUBSTITUTED PROGES- TERONES AND PROCESS THEREFOR J Allan Campbell, John C. Babcock, and William J.

Wechter, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Jan. 12, 1962, Ser. No. 165,954 20 Claims. (Cl. 260-3973) This invention relates to 16a,17u-methy1ene-6-substituted progesterones, intermediates therefor and processes XIII, XIV, 'XVI and XVII 3,086,029 Patented Apr. 16, 1963 for the production thereof. It is particularly concerned with 16a, 17 a-methylene-6a-methyl-4-pregnene-3,ZO-dione, 16:1,17 a methylene-6a-fluoro-4-pregnene-3,20-dione, 16a, 17a-methy1ene-6a-chloro-4-pregnene-3,ZO-dione and the corresponding A A and A -derivatives thereof. The present invention also relates to the corresponding compounds possessing 11(0: and fl)-hydroxy and ll-keto substituents. The 9oc-fl11010 analogues of all of the aforesaid compounds and intermediates therefor are also embraced within the scope of this invention.

The compounds of this invention and a process of production thereof are illustratively represented by the following sequence of formulae:

to XVIII, XIX, XX and XXI toV VIII

XII

com V from XIXc to XIXQ and XXII from XIX XIXc (wherein ll-QH is a) wherein R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine; R is selected tom the group consisting of hydrogen and the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive; R" is hydrogen or lower-alkyl; n is an integer selected from the group consisting of one and two; X is chosen from the group consisting of fluorine and chlorine; X is a halogen chosen from the group having an atomic weight from 35 to 127, inclusive, i.e., chlorine, bromine and iodine; X" is a halogen chosen from the group having an atomic weight from 19 to 127, inclusive, i.e., fluorine, chlorine, bromine and iodine; Ac is the acyl radical of an organic carhoxylic acid, preferably a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive; the broken lines appearing in Formula XIX and in Formulae XXII to XXVI, inclusive, represent A and A -double bonds, which may or may not be present in each of the formulae and represent A A, A and A -compounds; is a generic expression denoting on and ,8 bonds and mixtures thereof.

The novel compounds of this invention and the intermediates therefor possess valuable pharmacological properties, particularly progestational, anti-estrogenic, gonadotropin inhibiting, and anti-inflammatory. The compounds represented by the formula CH; (i= OH: I

A i R wherein R is selected from the group consisting of methyl, fluorine and chlorine and the broken lines represent A and A -doub1e bonds which may or may not be present and represent A A A and A -compounds, are effective progestational agents which are useful in the treatment of functional uterine bleeding and 'dysmenorrhea; they are also advantageously employed either alone, or in combination with an androgen (e.g., 17-methyltestosterone, testosterone cyclopentylpropionate), or an estrogen (e.g., 17-ethinylestradiol 3-methyl ether, estradiol cyclopentylpropionate) in maintaining pregnancy and regulating fertility in valuable domestic animals. The compounds repwherein R is selected from the group consisting of hydrogen, methyl, fluorine and chlorine, the broken lines are as in Formula A, above, X is selected fnorn the group consisting of hydrogen, chlorine, bromine and fluorine and Y is selected from the group consisting of the fi-hydroxymethylene radical the u-hydroxymethylene radical and the carbonyl radical C=O), are effective progestation-al agents useful in the treatment of functional uterine bleeding and dysmenorrhea; their use is beneficial in the maintenance of pregnancy and regulation of fertility in valuable domestic animals. In addition, the compounds embraced by Formula B possess marked anti-inflammatory activity and are effective in the treatment of various inflammatory conditions of the skin, respiratory tract, bones and internal organs, contact dermatitis, rheumatoid arthritis and allergic reactions; the latter condition is especially responsive to topical application of the aforesaid compounds.

The compounds of Formulae A and B can be prepared and administered to mammals, birds, and animals in a wide variety of oral and parenteral dosage forms, singly, or in admixture with other coacting compounds. They can be associated with a carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosage. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups or elixirs.

The novel 16a,17oa-methylene-G-substituted-progesterones (V) of the present invention are prepared by sev-eral processes, employing the routes and methods disclosed in (l) and (2), below.

(1) (a) 3/3-hydroxy-6-methyl-5,l6-pregnadiene-20-one (I) (prepared as in Example 11 of US. Patent 2,871,246) is reacted with diazomethane after the manner of Wettstein (Helv. Chim. Acta 27, 1803 [1944]) to produce the corresponding 16( 17 )-diazornethane adduct, 3fl-hydroxy- 6-methyl-16a:17w(2 :3 -diazacyclopent 2 -eno)-pregn- 5-en-20-one (II). The thus produced adduct (II) is decomposed by heating or by reaction with a strong acid, e.g., perchloric acid or boron trifluoride ethenate, to produce 16a,l7oz methylene-SB-hydroxy-6-methyl-5-pregnen- 20-one; acylation of this compound, e.g., with the anhydride of a hydrocarbon carboxylic acid such as acetic anhydride, yields 16a,17a-methylene-3fi-hydroxy-G-methyl- S-pregnen-ZO-one 3-acylate (III). The 3-acyl group of a compound represented by III is readily converted to 3,6- hydroxy; thus, 16a,17u-methylene-3p-hydroxy-6-methyl- 5-pregnen-20-one (IV) is prepared, e.g., by heating a compound of Formula III in methanol containing a strong mineral acid. Oxidation of the 3fl-hydroxy group of the compound of IV, yields 16a,17u-methylene-6a-methyl-4- pregnene-3,20-dione (V).

(b) The 6-methy1 compounds of Formula V can also be produced from the starting material (I) by an alternative procedure. This method comprises oxidation of the 313- hydroxy group of 3fi-hydroxy-6-methyl-5,16-pregnadiene- 20-one (I) to produce 6a-methyl-4,16-pregnadiene-3,20- dione (VI); the thus produced A -3-keto compound (V1) is converted to the corresponding 16(17)-diazomethane adduct (VII) by the method of Wettstein cited in (1) (a), above; the thus producedl6(17)-diazomethane adduct of 6a-methyl-4,16-pregnadiene-3,20-dione (VII) is decomposed by heating or by reaction with a strong acid, such as perchloric or boron trifluoride etherate, to yield, directly, l6a,l7a methylene-6u-methy1-4-pregnene-3,20-dione (V) and a byproduct, 6a,l6-dimethyl-4,l6-pregnadione-3,20-dione (Va).

(2) (a) The compounds of Formula V, wherein R .9, is fluorine or chlorine, are prepared from the known compounds of Formula VIII in accordance with the method of US. Patent 2,838,528. 3,B-hydroxy-5,16-preg nadiene-ZO-onev (VIII) or the corresponding 3-acylat e thereof, is convertedto 1 6-dehydro-3B-hydroxy or 3B- acyloxy-a,6u.-oxidopregnan-20-one (IX) with a peracid (e.g., performic, peracetic or perbenzoic); treating the compounds of Formula IX with hydrogen fluoride; hydrogen chloride or other fluorinating and chlorinating agents yield the corresponding 16-dehydro-3fi,5e-dihydroxy-6B-fluoro (or chloro) pregnan--one (X) or the 3 fi-acylate thereof; the 3 B-acylate is used, hydrolyzing the said 16-dehydro-6B-fiuoro (or chloro)-3fl-acyloxy-5a-hydroxypregnan-ZO-one (X) under acid conditions, for example with boron trifluoride or boron trichloride, yields l6-del1ydro-6[3fluoro (or chloro) 3 5,5 a-dihydroxypregnan- ZO-one (X); treating the l6-dehydro-65-fluoro (or chloro)-3fl,5ot-dihydroxypregnan-20-one (X) with an oxidizing agent such as sodium dichromate in acetic acid gives 16-dehydro-5a.-hydroxy-6B-fiuoro (or chloro) pregnane-3,20-dione (XI); dehydrating the thus obtained 16-dehydro 5a hydroxy-Gfl-fluoropregnane 3,20-dione (XI) with a base, or preferably with an acid, yields 6,6-fluoro (or chloro)-4,16-pregnadiene-3,20-dione (16- dehydro 613 fiuoro (or chloro) progesterone) (XII), which is isomerized by acid (or base) to the corresponding 6a-fluoro (or chloro) compound (XII). Oxidizing 16-dehydro-6p-fluoro 3fi,50t dihydroxypregnan ZO-one (X) by the Oppenauer process produced '16-dehydro-6- fiuoroprogesterone (XII) directly. The 6-halo compounds of Formula XII are converted to the 16(17 )-diazomethane adducts of 6-fiuoro (or chloro)-4,16-pregnadiene-3,20-dione (XIII) by the method of Wettstein cited in (1) (a), above; decomposition of the thus produced adducts (XIII) to yield l6a,17et-methylcne-6ufluoro (or chloro)-4-pregnene3,20-dione (V) is carried out in the manner disclosed in (1) (a) or (1) (b), above.

([1) The compounds of Formula V, wherein R is fluorine or chlorine, can also be prepared 'by an alternative method that does not entail the production of the 16(17)- diazomethane adduct (XIII) of (2) (a), above. This process also utilizes the procedures of US. Patent 2,838,- 528 for the substitution of a tfluoro (or chloro) atom at the 6-position of the steroid nucleus, but employs a starting material containing the 16a,17 t-methylene group. By following the procedures disclosed in (2) (a), above, 16a,l7a-methylene-3f3-1ydroxy (or acyloXy)-5-pregnen- 20-one (XIV) (Ber. 93, 1714 [1960]) is converted to 16a,17u-methylene 35 hydroxy (or 3p-acyloxy)-5a,6etoxidopregnan-ZO-one (XV); the compounds represented by Formula XV are transformed to IMAM-methylene 6/3-fluoro (or chloro)-3fl-hydroxy (or acyloxy)-5a hydroXypregnan-20-one (XVI), which in turn are converted to 16a,17ot-methylene-5u-hydroxy-6fi-fiuoro (or chloro)- pregnane-3,20-dione (XVII); dehydration of 1604,17!!- methylene-5 -hydroxy-6B-fiuoro (or chloro) pregnanc- 3,20-dione (XVII) yields, respectively, 1-6ot,17a-6(a and B)-fiuoro-4-pregnene 3,20 dione (16u,17a-methylene-6 (a and B)-fiuoroprogesterone) (V) and 16a,17a-methylene-6a-chloroprogesterone (V).

The novel 16a,1la-methylene-6-substituted progesterones (V) of this invention are converted to the unsaturated derivatives thereof in accordance with the procedures well known in the steroid art. The compounds represented by Formula V when reacted with chloranil, in the manner disclosed in J. Amer. Chem. Soc. 79, 1257 (1957), yield the corresponding 16u,17a-methylene-6- substituted-6-dehydroprogesterones (XVIII), e.g., 16cc, 17oc-methylene-6a-fluoro 4,6 pregnadiene 3,20 dione (XVIII). The A -compounds embraced by Formula XVIII can be dehydrogenated with selenium dioxide to give the corresponding A -compound (XX), e.g., 16cc, 17m-methylene-6a-rnethyl 1,4,6 pregnatriene-3,20-dione (XX); preferably, they can be prepared by the 6-dehydrogenation 0f the corresponding AV -compounds (XXI) by reaction with chloranil. The A -compounds (XX) can also be prepared directly from the A -compounds of Formula V by reaction with chloranil at elevated temperatures in accordance with the method also set forth in J. Amer. Chem. Soc. 79, 1257 (1957). The A derivatives (XXI) of Formula V are produced by 1,2- dehydrogenation with selenium dioxide in the manner disclosed in US. Patent 2,971,886 and by dicyanodichlorobenzoquinone in the manner disclosedv in British Patent 852,847; e.g., in this manner 160:,17ot-II16I1'1Y16116-6amethyl-4-pregnene-3,20- dione (V) is converted to 160;, l7ct-methylene-6a-methyl 1,4 pregnadiene 3,20-dione (XXI).

The novel ma na-methylene compounds represented by Formula'e V, XVIII, XX and XXI (and also embraced by Formula A, above), in addition to possessing valuable therapeutic properties, are useful as intermediates in the production of the corresponding ll-oxygenated compounds designated by Formulae XIX, XIXa, XXV and XXVI and embodied in Formula B, above. For example, a compound represented by Formulae V, XVIII, XX and XXI can be or lla-hydroxylated with one of the many species of fungi known to oxygenate in that position, e.g., one from the order of Mucorales, Aspergillus, Penicillium, such as Rhizopus nigricans, Czmvularia [name or Cunninghamella blakesleeana, to produce a compound represented by Formula XIX.

An effective method of converting an llot-hydroxyipregnene compound or" Formula XIX to the corresponding 11,8-hydroxy epimer is readily available by adapting the procedures disclosed in US. Patent 2,968,655 for an analogous synthesis. In a similar manner, a 16ot,170: methylen -lie-hydroxyl-pregnene (XIX) is converted to the corresponding ll-keto compound (XIXa) by oxidation, e.g., with chromic acid, chromic anhydride or N- bromoacetamide in pyridine, according to the usual procedures, Well known in the steroid art; the thus produced- 4-pregnenes of Formula (X-IXa), e.g., 16a,17a-methyl ene-6-methyl-4-pregnene-3,11,20-trione (XIXa), :,17rxmethylene-6-fiuoro-4-pregnene 3,11,20 trione (XIXa), 16u,l7a-methylene 6 chloro-4-pregnene-3,l1,20-trione (XIXa) are diketalized, e.g., with ethylene glycol and p-toluenesulfonic acid to give, respectively, 16,I7amethylene-G-methyl 4 pregnene-Ii,11,20-trione 3,20-bis (ethylene ketal) (XIXb), 16a,l7ot-methylene-6-fluoro-4- pregnene-3,1l,20-trione 3,20-bis(ethylene ketal) (XIXb) and 1605,1705 methylene 6 chIcro-4-pregnene-3,l1,20- trione 3,20-bis(ethylene ketal) (XIXb); the compounds of Formula XIXb are reduced to their corresponding llfl-hydroxy analogues (XIXc), e.g., with lithium aluminum hydride; the compounds represented by Formula XIXc, such as 16a,17a-methylene-6-methyl-1lfi-hydrony- 4-pregnene-3,20-dione 3,20-bis0ethylene ketal) .(XIXc), 16w,17e-methylene-6-fluoro 11;? hydroxy 4-pregnene- 3,2D-dione 3,20-bis(ethylene =ketal) (XIXc), and 160:, 17a-methylene-6-chloro 11,8 hydroxy-4-pregnene-3,2=0- dione 3,204bis(ethylene ketal) (XIXc) are hydrolyzed, e.g., with a concentrated mineral acid such as sulfuric to yield, respectively, 16a,17a-methylene-6m-methyl-l1,8- hydroxy-4-pregnene-3,20-dione (XIX), 160t,170t-'methyI- ene-6a-iluoro-l1fi-hydroxy-4-pregnene 3,20-'dione (XIX) and 16cc,170L-H13lhYl6Il8-6ot-Chl010 11,6 hydroxy-4-pregnene-3,20-dione (XIX).

The lla-hydroxy and llfl-hydroxy compounds represented by Formula XIX can be converted to their ll-keto counterparts (XIXa) by oxidation, e.g., with chromic anhydride or N-bromoacetamide in pyridine, according to usual procedures.

Both the llotand llfl-hydroxy compounds of Formula XIX can be converted in known manner to their corresponding Qa-fluoro derivatives (XXV) by the series of reactions disclosed in U.S. Patents 2,852,511, 2,923,722, 2,924,612 and 2,957,894. The methods described in the aforesaid patents involve dehydration of the ll-hydroxy group, e.g., with N-bromoacetamide and anhydrous sulfur dioxide in pyridine or via the p-toluenesulfonate ester, to produce the corresponding M -compounds (XXII) which are then treated with a hypohalous acid, e.g., N- bromoacetamide, N-chlorosuccinimide or N-iodosuccinimide, in the presence of aqueous perchloric acid, to produce the corresponding 9a-halo-11B-hydroxy compounds represented by Formula X)GII; reaction of the 1606,1706- methylene-9a-halo-1Its-hydroxy compounds (XXIII) with a base, e.g., potassium acetate in acetone or sodium or potassium hydroxide in methanol, yields the corresponding 95,11fl-epoxides embraced by Formula XXIV; reaction of these 16a,17u-methylene-9,B,1lfi-epoxides (XXIV) with anhydrous or aqueous hydrogen fluoride at below room temperature produce the corresponding 9ot-fiuorollfl-hydroxy compounds represented by Formula XXV; the 16a,17u-methylene-9a-halo-1Iii-hydroxy compounds of Formulae XXV and XXIII can be oxidized to their corresponding ll-keto compounds (XXVI) with chromic acid or chromic anhydride. By following the above procedures, representative 16a,17a methylene 11B hydroxy compounds of Formula XIX are converted to their 9onfiuoro counterparts (XXV). In this manner,

16a,17a-methylene-11/3-hydroxy-4-pregnene-3,20-dione 16a,17a-methylene-1 1 B-hydroxy-6u-methyl-4-pregnene- 3,20-dione (XIX),

16a,17a-methylene-1 1B-hydroxy-6a-fiuoro-4-pregnene- 3,20-dione (XIX),

16a,17ix-methylene-1 1B-hydroxy-6a-methyl-1,4-pregnadiene-3,20-dione (XIX),

160;,170t-In6thY16I16-1 1B-hydroxy-6a-chloro-1,4-pregnadiene-3,20-dione (XIX),

16u,17u-methylene-1 1 B-hydroxy-6-1nethyl-4,6-pregnadiene-3,20-dione (XIX),

16u,17ot-methylene-1 1,B-hydroxy-6-fluoro-4,6-pregnadiene- 3,20-dione (XIX),

16,a17a-methylene-1lit-hydroxy-1,4,6-pregnatriene-3,20-

dione (XIX),

16oz, 17a-methylene-1 1B-hydroxy-6-methyl-1,4,6-pregnatri ene-3,20-dione (XIX),

16u,17ot-methylene-11fl-hydroxy-6-fiuoro-1,4,6-pregnatricue-3,20-dione (XIX) and 16:1,170t-I1161hYl6116-1 1;8hydroxy-6-chloro-1,4,6-pregnatriene-3,20-dione (XIX) yield, respectively,

16a,17ot-methylene-9a-fiuoro-11fi-hydroxy-4-pregneue- 3,20-dione (XXV),

16a,17a-methylene-9a-fiuoro-6ot-methyl-11/3-hydroxy-4- pregnene-3,20-dione (XXV),

16a,17a-methylene-6a,9a-difluoro-11/3-hydroxy-4-pregnene-3,20-dione (XXV),

16a,17ot-methylene-9ot-fluoro-6a-methyl-1 1fi-hydroxy-1,4-

pregnadiene-3,20-dione (XXV),

16a,17a-methylene-9or-fiuoro-6ot-chloro-11,B-hydroxy-1,4-

pregnadiene-3,20-dione (XXV),

16oz,17ot-methylene-9a-fiuoro-6-methyl-1 1 8-hydroxy-4,6-

pregnadiene-3,20-dione (XXV),

16a,17a-methylene-6,9a-difiuoro-11fl-hydroxy-4,6-pregnadiene-3,20-dione (XXV),

16a,17a-methylene-9a-fiuoro-11fi-hydroxy-1,4,6-pregnadiene-3,20-dione (XXV),

16a,17ot-methylene-9a-fiuoro-6-m'ethyl-1 1B-hydroxy-1,4,6-

pregnatriene-3,20-dione (XXV),

16a,17a-methylene-9a-fiuoro-6-chloro-11B-hydroxy-1,4,6-

pregnatriene-3,20-dione (XXV).

Example 1.16(17)-Diaz0methane Adduct f 3,3-H

dr0xy-6 -M ethy l- ,1 6-Pregnadiene-2 O-One [3 fi-Hydroxy- 6 -M ethyl-1 61x31 7a- (2 :3 -Diazacycl0pent-2 -en0) -Pregn- 5-En-20-0ne] (II) 25 g. of N-methyl-N-nitroso-N'-nitroguanidine was added in small portions over a period of about 20 minutes to a stirred chilled mixture of 250 ml. of ether and 70 ml. 'of aqueous 50% potassium hydroxide. The ether layer was decanted and the water phase washed several times with small fresh portions of ether. The combined ether solutions of diazomethane thus prepared were diluted to about 400 ml. with ether and 25 g. of 3fi-hydroxy-6- methyl-5,16-pregnadien-20-one (6 methyl 16 dehydropregnenelone) (I) (prepared in the manner disclosed in Example 11 of US. Patent 2,871,246) added. After stirring for a period of about 6 hours at room temperature, the excess diazomethane of the reaction mixture was decomposed by dropwise addition of acetic acid. This solution was washed successively with water, dilute hydrochloric acid, dilute sodium bicarbonate and again with water. After drying over magnesium sulfate, the solvent was removed leaving a crystalline residue. This product was triturated with acetone and then recrystallized from acetone to yield 7.8 g. of material with a melting point of 184 to 187 C. (with bubbling). A small amount of the product was recrystallized to give the pure 16(17)-diazomethane adduct of 3B-hydroxy-6-methyl-5,16-pregnadien-20-one, [3,B-hydroxy-6-methyl-l6a: 17Ot-(2 1 3 -diazacyclcpent-2 -eno)-pregn-5-en-20-one] (II) melting at to C. and a rotation [04], of +21 (chloroform).

Analysis.Calcd. for C H O N C, 74.55; H, 9.25; N, 7.56. Found: C, 74.31; H, 9.02; N, 7.82.

Example 2.16a,17a-Methylene-3fi-Hydroxy-6-Methyl- S-Pregnen-ZO-One 3-Acetate (III) 1 ml. of boron trifluoride etherate was added to a slurry (cooled in an ice bath) of 2 g. of the diazomethane adduct of 3fi-hydroxy-6-methyl-5J6-pregnadien-20-one (II) in 10 ml. of acetone. The solution became clear in a few minutes; after a period of about 30 minutes it was poured into water and extracted with methylene chloride. The extract was washed successively with water, dilute sodium hydroxide solution, again with water and dried. The solvent was removed from the extract leaving a yellow non-crystalline residue. The residue was dissolved in 5 m1. of pyridine and 3 ml. of acetic anhydride added to give a blood-red solution. This solution was warmed to about 50 C. for a period of about 30 minutes, poured into water and extracted with methylene chloride. The extract was washed successively with dilute hydrochloric acid, dilute sodium hydroxide and water. It was then dried and poured onto a 150 g. column of Florisil (synthetic magnesium silicate) packed wet with Skellysolve B (hexanes). The intense color of the methylene chloride extract was absorbed in the first two inches of the column. Gradient elution with mixtures of 5 l. of 2% acetone- Skellysolve B, 5 l. of 10% acetone-Skellysolve B (400 ml. portions) gave crystalline residues in fractions 4 and 5. These fractions were combined and recrystallized from aqueous methanol to yield 20 mg. of 16w17tx-methylene- 3/3-hydroxy-6-methyl-5-pregnen-20-one 3 -acetate (III) with a melting point of 136 to 141 C. The infrared spectrum of the compound shows absorption (C==) at 1733 and 1675 cm.- and (C=O) at 1240 cm.- Neither terminal methylene nor A -methyl absorptions were observed.

Analysis.Calcd. for C H O C, 78.08; H, 9.44. Found: C, 78.74; H, 9.70.

Example 3.-16a,1 7a-Methylene-jfi-Hydroxy-fi- M ethyl-5 -Pregnen-20-One (IV) 0.5 gm. of 16a,17a-methylene-3fi-hydroxy-6-methyl-5- pregnen-ZO-one 3-acetate (III) in 20 ml. of methanol and 0.15 ml. of concentrated hydrochloric acid is refluxed for a period of about 1 hour. About half of the methanol is evaporated under a stream of nitrogen. The product is flooded out with Water, collected, dried and recrystallized from acetone to yield 1606,1705 methylene 3/3 hydroxy-6-methyl-5-pregnen-20-one (IV).

Example 4.16ot,17 x Methylene-6u-Methyl-4-Pregnene- 3,20-Dion e (16 7e-Methylene 60 Methylprogesterone) (V) A solution of g. of 16ml70methylene-3eahydroxy-6- methyl-5-pregnen-ZO-one (IV) in 15 m1. of cyclohexanone and 35 ml. of toluene is boiled for a few minutes to remove any traces of water and then 2.5 g. of aluminum isopropoxide added. This solution is stirred under reflux for a period of about 35 minutes, cooled, diluted with a little methylene chloride and then washed successively with dilute sodium hydroxide, salt water, dilute hydrochloric acid and then twice with salt Water. The solution is dried and then chromatographed on a 200 g. column of Florisil. The product is eluted with mixtures comprising Skellysolve 13 containing 6 to 8% of acetone; recrystallization from a mixture of hexanes and acetone yields light-colored, crystalline 16oc,l7ct methylene 6amethyl-4-pregnene-3,20 dione (V).

Example 4A .16or,17a-Met/zylene-4-Pregnene-3,20- Dione (16 7a-Merhyleneprogesterone) (V) Following the procedure of Example 4, but substituting 16a, 170a methylene-3B-hydrcxy-S-pregnen-20-one (XIV) Example 5 .-6 oc-M ethyl-4,] 6-Pregnadiene-3,20-Di0ne (6 a-M ethyl-1 6 -D ehydroprogesterone) VI) A solution of 5 g. of 3,6-l1ydroxy-6-methyl-5,16-pregnadien-20-one (I) in 15 ml. of cyolohexanone and 35 ml. of toluene is boiled for a few minutes to remove any traces of water and then 2.5 g. of aluminum isopropoxide added. This solution is stirred under reflux for a period of about 35 minutes, cooled, diluted with a little methylene chloride and then Washed scccessively with dilute sodium hydroxide, salt water, dilute hydrochloric acid and then twice with salt water. The solution is dried and ten chromatographed on a 200 g. column of Florisil. The product is eluted with mixtures comprising Skellysolve B containing 6 to 8% of acetone; recrystallization from a mixture of hexanes and acetone yields light-colored, crystalline 6ix-methyl-4,l6 pregnadiene-3,20 dione (VI).

Following the procedure of Example 5, but employing 3,8-hydroxy-5,l6-pregnadien-20-one as starting material, yields 4, 1 G-pregnadien-3,20-dione.

Example 6.-16(17)-Diaz0methane Adduct of Get-Methyl- 4,16 Pregnadiene 3,20 Dione [6a-Methyl-16az17a- (2 :3 Diazacyclopent 2 E110) Pregn-4-Ene-3:20-

Dione] (VIZ) 27.5 g. of N-methyl-N-nitroso-N-nitroguanidine was added in small portions over a period of about 20 minutes to a stirred chilled mixture of 270 ml. of etherand 75 ml. of aqueous 50% potassium hydroxide. The ether layer was decanted and the water phase Washed several times with small fresh portions of ether. The combined ether solutions of diazomethane thus prepared was diluted to about 500 ml. with ether and 20 g. of 6ot-methyl-4,16- pregnadiene-3,20-dione (owmethyl- 1 6 d'ehydroprogesterone) (VI) added. After stirring at room temperature for about 18 hours, the excess diazomethane was decon posed by dropwise addition of acetic acid. The reaction mixture was washed with water and dried. After removal of the solvent, the residue was .triturated with ether and crystallized from acetone to give 12.2 g. of the product melting at 159 to 162 C. (decomposition). Two further crystallizations from acetone yielded the pure product, the l6(17)-diaZomethane adduct of 6u-methyl-4,16-pregnadiene-3,20-dione [6tt-methyl-l6ml7a (2 :3 -diazacyolopent 7 2 eno)-pregn-4-ene-3:ZO-dione] (VII) with a melting point 0 5159 to 162 C. (decomposition), rotation [aj of +137 (chloroform) and Analysis.Calod. for C H O N C, 74.96; H, 8.75; N, 7.60. Found: C, 75.06; H, 9.28; N, 7.88.

Following the procedure of Example 6, but substituting 4,16-pregnadiene-3,20-dione as starting material, yields the 16(17)-diazornethane adduct of 4,16-pregnadiene- 3,20-dione.

Example 7.] 6 (1,1 7 or M ethylene-6 Ol-M ethyl-4-Pregnene- 3,20-Di0ne 1 6 0a,] 7 a M ethylene-6 a-M ethyl progesterone) (V) and 6a,] 6-Dimethyl-4,]6-Pregnadiene 3,20- Diolze (611,1 6-Dimethy [-1 6 -Dehydr0progesler0ne (Va) 1 g. of the 16(17)-diazomethane adduct of 6a-methyl- 4,16-pregnadiene-3,20-dione (VII) was added in portions to a solution of 0.4 ml. of 70% perchloric acid in 21 ml. of acetone at a temperature of about 50 C. Several minutes after the addition of the last portion, the solution was cooled, poured into ice-Water and extracted with methylene chloride. The extract was successively Washed with Water, dried, filtered and chromato-graphed on a 200 g. column of Florisilpacked wet with Skellysolve B. Gradient elution with 5 l. of 2% acetone in Skellysolve B and 5 l. of 8% acetone in Skellysolve B (400 ml. fractions collected) gave the desired cycloprop'ane in fractions 15 to 19. These fractions were combined and recrystallized from a mixture of acetone and Skellysolve B to yield 0.43 g. of product melting at 136 to 139.5 C. Another recrystallization from the same pair of solvents gave 0.35 g. of 16a,17a-methylene-6a-methyl-4-pregnene- 3,20-dione (V) with a melting point of 138 to 140 C., rotation [rd of +188 (chloroform),

k312i? 241 m (e=16,350) and a negative ttetranitromethane test.

Analysis.-Calcd. for C H O C, 81.13; H, 9.47. Found: C, 81.47; H, 9.57.

Fractions 21 to 26 contained the A -16-methyl product and were combined and recrystallized three times from a mixture of acetone and Ske'llysolve B to yield 30 mg. of 6u,l6-dimethyl-4,16-pregnadiene3,20-dione (Va) with a melting point of 189 to 192 C.,

ntonin 435 my, (e=23,845)

and a positive tetranitromethane test.

Analysis.-Calcd. for C H O C, 81.13; H, 9.47. Found: C, 81.27; H, 9.45.

Example 8. 16 Dehydro 3 8-Hydroxy-5afla-Oxiclopregmzn 20 One (16 Dehydr0-5u,6a-Oxid0pregnenelone) (IX) Example 9. 16 Dehydro 3fi-ACEZOXY-5ot,6u-O.Xid0

pregnan 2010112 (16 Dehydro-Sa,6a-Oxid pregnenelone 3fl-Acetate (IX) 16-dehydropregnenelone 3e-acetate (3{3-acetoxy-5,16- pregnadiene-ZO-one) (VIII) is treated with peracetic acid in the same manner as described in Example 8 to give 16-dehydro-3p-acetoxy-5u,6a-oxidopregnan-20-one (IX).

Alternatively, l6-dehydro-3B-acetoxy-5a,6a-oxidopregnan-20-one (IX) is obtained in nearly quantitative yield by treating 16-dehydro-3B-hydroxy-5a,6a-oxidopregnan- 20-one (IX) (from Example 8) with acetic anhydride in pyridine.

Similarly, other 3/3-esters of 16-dehydro-313-hydroxy- 5oz,6zx-0Xid01316gnflD-20-On6 (IX) are prepared by treating the corresponding unesterified 3fi-hydroxy compound in pyridine solution with the anhydride or acyl halides of organic carboxylic acids, particularly hydrocarbon carboxylic acids containing from one to twelve carbon atoms, inclusive. Representative 3,8-esters thus prepared include in particular, the propionate, butyrate, isobutyrate, valerate, isovalerate, hexanoate, heptanoate, octanoate, benzoate, phenylacetate, phenylpropionate, propiolate, crotonate, B-cyclopentylpropionate, tertiary butylacetate, toluate, 2-furoate, benzenesulfonate, toluenesulfonate, and the like of 16-clehydro-3fi-hydroxy-5a,6aoxidopregnan-ZO-one (IX).

Example 10.1 6 -D ehydr-6 ,E3-Flu0r0-3 p-A cetoxy-S a H ydroxypregnan-ZO-One (X) In a fifty ml. polyethylene bottle cooled with a Dry Iceacetone mixture is placed 6.9 g. of anhydrous hydrogen fluoride, followed by slow addition of ml. of chilled chloroform (stabilized with a trace of alcohol) and 13.24 ml. of tetrahydrofuran. To this is added 4 g. of 16- dehydro-3,8-acetoxy-5ot,6ot-oxidopregnan-20-one (IX) in 25 ml. of chilled chloroform giving a violet solution which was kept for two hours at C., then poured into excess aqueous sodium bicarbonate with stirring. The thus obtained mixture is extracted With methylene chloride and the methylene chloride solution was washed with water and evaporated to dryness. The residue thus obtained is crystallized from methylene chloride-ethyl acetate mixture to yield light-colored crystalline 16-dehydro- 6/3-fluoro-3fi-acetoxy-Su-hydroxypregnan-20-one (X).

Similar results are obtained using smaller amounts of hydrogen fluoride as shown in the following procedure.

A mixture of 0.60 g. of anhydrous hydrogen fluoride and 2.80 g. of 16-dehydro-3B-acetoxy-5a,6a-oxidopregnan-ZO-one (IX) in 24 ml. of methylene chloride is kept for about four hours at room temperature, then 0.6 ml. of pyridine is added and the mixture is evaporated to dryness. The thus obtained residue is triturated with ether to give crystalline 16-dehydro-6B-fluoro-3 3-acetoxy- 5ot-hydroxypregnan-20-one (X).

Example 11.--16-Dehydro-QB-Chl0r0-3p-Acetox1y-5u- Hydroxypregnan-ZO-One (X) A slow stream of gaseous hydrogen chloride is passed through a solution of 4 g. of l6-dehydro-3 8-acetoxy- 5a,6a-oxidopregnan-20-one (IX) in 50 ml. of ice-cold methylene chloride for a period of about 1 hour. The resulting solution is allowed to stand at room temperature for a period of about 4 hours then neutralized with pyridine. The methylene chloride is removed by evaporation and to the slurry thus obtained, water is added. The mixture thus obtained is filtered and the solid material remaining is washed thoroughly with water. The solid material is then recrystallized from acetone to yield light-colored, crystalline 16-dehydro-6,o-chloro-3341cctoxy-5u-hydroxypregnan-20-one (X).

A mixture of 7.3 g. of anhydrous hydrogen fluoride in 5 ml. of chloroform and 14 ml. of te-trahydrofuran is cooled in a Dry Ice-acetone bath and a solution of 4 g. of 16 dehydro 3B-hydroxy-5a,6ot-oxidopregnan-20-one (IX) in ml. of chloroform is added. This reaction mixture is kept at -10 C. for about 2.5 hours and is then poured into excess aqueous sodium bicarbonate solution. The resulting mixture is extracted with methylene chloride and the methylene chloride extract washed with water and evaporated to give a solid residue, which is recrystallized from methanol-ethyl acetate mixture to give 16 dehydro-6B-fluoro-3fl,Sa-dihydrQXy-pregnan-ZO- one (X).

In an alternative method of preparation, a mixture of 100 mg. of 16-dehydro-6 8-fiuoro-3fi-acetoxy-5ot-hydroxy pregnan-ZO-one (X) from Example 10, 2.5 ml. of methanol and 0.1 ml. of boron trifluoride-etherate is heated under reflux for about fifteen minutes, then is concentrated to 1 ml. and diluted with water to give 75 milligrams of a precipitate consisting of crude l6-dehydro- 6I3-fiuoro-3{3,5ot-dihydroxy-pregnan-ZO-one (X).

Example 13.-16 Dehydro-ofi-chlore-3,6,5a-Dihydr0r pregnan-ZO-One (X) A solution of 6 g. of 16-dehydro-3fi-hydroxy-5m,6otoxidopregnan-20-one (IX) (prepared as in Example 8) in 50 ml. of chloroform is cooled in an ice-salt bath and saturated with gaseous hydrogen chloride. After a period of about one hour, the reaction mixture is purged with nitrogen. The reaction mixture is then washed with water, dilute sodium carbonate solution and again with water and then dried over magnesium sulfate. The solvent is evaporated leaving an amorphous residue of 16- de'nydro 65-chloro-3fi,Sa-dihydroxypregnan-ZO-one (X) which retained chloroform is a solvated form. This residue can be used without further purification in Examle 15. P If desired, by drying at 60 C. to 100 C. under reduced pressure, the chloroform solvate of l6-dehydro-6fi-ch1oro- 313,5a-dihydroxypregnan-ZO-one (X), described above, is converted to 16dehydro6fl-chloro-3fi,Sa-dihydroxypregnan-ZO-one (X).

Example I4.-16-Ddhydro-5a-Hydr0xy-6 3-Flu0r0pregname-3,20-Di0ne (XI) One gram of 16-dehydro-3fi,5a-dihydroxy-fifi-fluoropregnan-ZO-one (X) is added to 25 ml. of acetic acid and immediately 1 g. of sodium dichromate dihydrate dissolved in 10 ml. of acetic acid is added while the reaction mixture is stirred and cooled in a cold water bath. The reaction mixture is allowed to stand about 18 hours at room temperature, then 2 ml. of methanol is added to destroy excess oxidant and the reaction mixture is poured into water to give crystalline 16-dehydro-5a-hydroxy-6B- flu opregnane-3,20-dione (XI).

Example 15.---] 6 -Dehydro-5 a-H ydroxy-6 S-Chloropregnane-3,20-Di0ne (X1) To the residue of 16-dehydro-6B-chloro-3fi,Sa-dihydroxypregnau-ZO-one (X) from Example 13, 6 g. of sodium dichromate in 60 ml. of acetic acid is added with cooling in a cold water bath. The thus obtained solution is allowed to stand without further cooling for about 2 hours and yields a precipitate. The thus formed precipitate is collected, first washed with acetic acid, then ether and dried. The thus obtained residue is recrystallized from ethyl acetate-acetone to yield light-colored, crystalline 16 dehydro 5o: hydroxy 6,3 chloropregnane-3,20-dione (XI).

xample 16.--6;3 Fluoro 4,16 Pregnadiene 3,20- Dione and 6ot-Flu0r04,16-PregnadieIze-3,20-Dione (16- Dehydr0-6 3-Flu0ropr0gester0ne and 16-Dehydr0-6u- Fl uoroprogesterone) (XII) Two grams of 16-dehydro-5a-hydroxy-6/S-fluoropregnane-3,20-dione (XI) is suspended in 200 milliliters of chloroform (containing 0.75 percent alcohol) at room temperature and anhydrous hydrogen chloride gas passed through the mixture for about thirty minutes. After two minutes, a pale yellow solution is obtained. Following the hydrogen chloride treatment, a stream of nitrogen is passed through the solution for about fifteen minutes, and the solution is then washed with cold water and with five percent aqueous sodium bicarbonate. The thus obtained chloroform solution is evaporated and gives as residue a pale glass. The crude mixture is placed on g. of Florisil (synthetic magnesium silicate) and eluted with 250-milliliter fractions of acetone in petroleurn ether (thirty to sixty degrees). With four to five percent acetone, a mixture of l6-dehydro-6u-fiuoroprogesterone (XII) and 16-dehydro-6,8-fiuoroprogesterone (XII) is obtained which on fractional crystallization from 17 a mixture of ether and Skellysolve B hexanes gives pure I6-dehydro-6fl-fluoroprogesterone (XII), and iii-dehydro- 6ot-fluoroprogesterone (XII).

Example 17.-I6-Dehyclr0-6fl-Flu0r0progesterone (XII) Two grams of 1-6-dehydro-5e-hydroxy-6p-fluoropregname-3,20-dioi1e (XI) suspended in 400 ml. of 95 per cent ethanol containing nine drops of concentrated hydrochloric acid is refluxed for about fifteen minutes, and 100 ml. of dioxane and six drops of concentrated hydrochloric acid are then added and the starting material dissolved. The solution is heated at reflux for about two and one-half hours, and aliquots are taken which show by melting points that practically no dehydration occurs. Qne ml. of concentrated hydrochloric acid is then added to the reaction mixtureand refluxing is continued for about an additional three and one-half hours. The mixture is then concentrated to one-half volume by evaporation under diminished pressure, diluted with 100 ml. of water, and further concentrated until crystallization occurs, giving a mixture which on fractional crystallization from a mixture of methylene chloride and methanol gives crystalline 1 6-dehydro-6 8fluoroprogesterone (XII).

Example 1 8.-] 6-D ehydro-6ot-Flu0ropr0gester0ne (XII From 1 6-D ehydro-6,8-Flur0pr0gester0ne (XII A solution of 16-dehydro-6,8-fluoroprogesterone (XII) in a mixture of ethanol and aqueous hydrogen chloride is heated under reflux for about thirty minutes, and the mixture is then poured into a large excess of water and the precipitated material collected by filtration and recrystallized to give pure 16-dehydro-6a-fiuoroprogesterone (XII).

1 Example 19.-6a-Chl0r0-4,16-Pregnadiene-3,2O-Dione (1 6-Dehydr0-6u-Ci2loroprogesterone) (X 11 A solution of 4 g. of 16-dehydro-5a-hydroxy-6p-chloropregnane-3,20 -dione (XI) (prepared in the manner disclosed in Example 15) in 50 ml. of chloroform and 0.5 ml. of absolute ethanol is cooled in an ice-salt bath and saturated with gaseous hydrogen chloride. After a period of about 3 hours, the reaction mixture is removed from the cooling bath and'purged with nitrogen. The reaction mixture iswashed with water, then dilute aqueous sodium bicarbonate solution, dried over magnesium sulfate and the solvent evaporated to give a residue.

The thus obtained residue is then crystallized twice from p a mixture of acetone and Skellysolve B to yield 16-dehydro-6u-chloroprogesterone (XII).

Example 20.16(17)-Diaz0methane Adduct of 60:-

F loom-4 ,1 6 -Pregnadiene-3,2 O-Dione [6 a-Fluoro-l 6 a. 17cc (2 :3 -Diazacycl0pent 2 Eno) Pregn 4 Ens-3:20-Dione] (XIII) An ether. solution of diazomethane (prepared in the manner described in Example 6) is diluted to about 500 ml. with ether and 20 g. of 6a-fluoro-4,l fi-pregnadiene- 3,20 dione (16 dehydro 6a fluoroprogesterone) (XII) (produced in the manner disclosed in Examples 16 or 18) added. After stirring at room temperature for about 18 hours, the excess diazomethane is decomposed by dropwise addition of acetic acid. The reaction mixture is, washed with water and dried. After removal of the solvent, the residue is triturated with ether and crys tallized from acetone to give the 16(17)-diazomethane adduct of 6a-lluoro-4,l6 pregnadiene-3,ZO-dione [6afiuoro 16oc1l7ot (2 :3 diazacyclopent 2 eno)- pregn-4-ene-3 ZU-dione] (XIII) Following the procedure of Example 20, but employing 6/3-fiuoro-4,l'6-pregnadiene-3,20dione (XII) (produced in the manner disclosed in Example 17) as starting material, yields the 16(l7)-diazomethane adduct ofofifluoro-4,16-pregnadiene-3,20-dione (XIII).

Example 21.--16(17)-Diaz0methane Adduct of 6a- Chl0r0-4,16-Pregnadiene-3,20-Dione [6ot Chl r0-1 61x. 17a-- (2 :3 Diazacyclopent 2 Eno Pregn 4- Ene-3r20-Dione] (XIII Following the procedure of Example 20, but substituting 6a-chloro-4,16'-pregnadiene-3,20 dione (XII) (produced in the manner disclosed'in Example 19) as starting material, yields the 16(17)-diazomethane adduct of 6achloro-4,l 6 pregnadiene-3,ZO-dione (XIII).

Example 22 1 6 11,1 7a-Methylene-6m-Flu0r0-4-Pregnene- 3,20 Dione (a,.l7ot Methylene 6a Fluoroprogesrerone) (V) 1 g. of the 16(17)-diazom'ethane adduct of '6tx-flll0l0- 4,16-pregriadiene-3,20-dione (XIII) is added in portions to a solution of 0.4 ml. of 70% perchloric acid in 20 ml. of acetone at a temperature of about 5 0 C. Several minutes after addition of the last portion, the solution is cooled, poured into'ice water and extracted with methylen-e chloride. The extract is successively washed with Water, dried, filtered and chromatographed on a 200 g.

column Florisil packed'wet with Skellysolve B. Gradient *elution with s 1. of 2% acetone'in Skellysolve B and 5 l. of 8% acetone in'Skelly'solve B (400 ml. fractions collected) gives the desired cyclopropane product. The

Example 23 .-1 6 04,1 7a-Methylene-6a-Chloro- I-Pregnene- 3,20-Di0ne (1 6 0a,] 70t-M ethylene 6 0t Chloroprogesterone) V) Following the procedure of Example 22, but substituting the 16(- 1' 7)-diazomethane adduct of dot-chloro- 4,16pregriadiene-3,ZO-dione (XIII) (from Example 21) as starting material, yields crystals of 16a,17a-methylene- -6d-chlorol-pregnene-3,20 dione (V).

Example 24.-16a,1 7a-ll Iethylene 3B HydrOxy-Safiu- Qxidopregnan 20 One (160:,170; Methylene-Smoot- Oxidopregne'nelone (XV) A reaction mixture comprising 20 g. of 160:,17ocmethylene-3 18-hydroxy-5 -pregnen-20-one 1 6ot,17ot-II16II1- ylenepregnenelone) (XIV) (Ber. 93, 1714 [1960]), 4 g. of 'anhydrous'sodium acetate and 20 ml. of 40% peracetic acid in 400 ml. of chloroform is stirred 2 hours at a'temperature between about 0 to 4 C. The reactionmixture is then washed with water and aqueous sodium bicarbonate and evaporated to near dryness. The thus obtained residue is crystallized from a mixture of methylene chloride and acetone to give the desired product. Recrystallization from the same solvent pair yields 16a,17a-methylene-3B-hydroxy 501,60; oxidopregnan- 20-one (XV).

Example 25.-16ot,17oc Methylene 3B ACfOXy-5ot,6ct-

Oxidopregnari- 20 One (160:,17a Methylene-Smoot- Oxidopregnenelone 3B-Acetate) (XV) 16a,17x-methylene 3 8 acetoxy 5 -*pregnen-20-one (16e,17or-methylenepnegnenelone 3fi-acetate) (XIV) (Ber. 93, 1714 [1960]) is treated with peracetic acid in the same manner as described in Example 24 to give 160:,17arnethylene-3B-acetoxy-Su,6a-oxidopregnan-20-one (XV).

Alternatively, 16a,l7a-methylene 35 acetoxy-5a,6ocoxido'pregnan-20 one (XV) is obtained in nearly quantitative yield by treating 16a,l7a-methylene-3[3-hydroxy- 19 5u,6a-oxidopregnan-20-one (XV) (from Example 24) with acetic anhydride in pyridine.

Similarly, other 3;8-esters of 16a,l7a-methylene-3fihydroXy-Sa,6a-oxidopregnan-20-one (XV) are prepared by treating the corresponding unesterified BB-hydroxy compound in pyridine solution with the anhydride or acyl halides or organic carboxylic acids, particularly hydrocarbon carboxylic acids containing from one to twelve carbon atoms, inclusive. Representative 3,8-esters thus prepared include in particular, the propionate, butyrate, isobutyrate, valerate, isovalerate, hexanoate, heptanoate, octanoate, benzoate, phenylacetate, phenylpropionate, propiolate, crotonate, p-cyclopentylpropionate, tertiary butylacetate, toluate, 2-furoate, benzenesulfonate, toluenesulfonate, and the like of 16a,17a-methylene-3/3-hydroxy-5a,6a-oxidopregnan-20-one (XV).

Example 26.-I6a,17a-Methylene-6 3-Fluoro-3fl-Acetoxy- 5 a-H ydroxypregnan-ZO-One (XVI) Following the procedure of Example 10, but substituting 16a,l7a methylene-3fl-acetoxy-5a,6a-oxidopregnan- 20-one (XV) (from Example 25) as starting material, yields crystalline 16a,17a-methylene-6B-fluoro-3/3acetoxy- 5a-hydrOXy-pregnan-ZO-one (XVI).

Example 27.16a,1 7a-Methylene-6p-Chloro-Sfi-Aeetoxy- 5 oc-H ydroxy pregnan-ZO-One (XVI) Following the procedure of Example 11, but substituting 16a,17a methylene-3fi-acetoxy-5a,6a-oxidopregnan- 20-one (XV) (from Example 25) as starting material, yields light-colored, crystalline l6a,17a-methy1ene-6fichloro-Sfi-acetoxy-Sa-hydroxypregnan-20-one (XVI).

Example 28.I6a,17a-Methylene 613 Fluor-3B,5a-Dilzydroxypregnan-ZO-One (XVI) Following the procedure of Example 12, but substituting 16a,17a-methylene-3B-hydroxy-5a,6a-oxidopregnan- 20-one (XV) (from Example 24) as starting material, yields light-colored crystals of 16a,l7a-methylene-6fifluoro-35,5a-dihydroxypregnan-20-one (XVI).

Example Z9.]6oc,l 7u-M ethylene 6B Chl0r0-3 3,5a-Dihydroxypregnan-ZO-One (XVI) Following the procedure of Example 13, but substituting 16a,17a-methylene-3B-hydroxy-5a,6a-oxidopregnan- 20-one (XV) (from Example 24) as starting material, yields 16a,l7a methylene 6p chloro-3B,5a-dihydroxypregnan-ZO-one (XVI).

Example 30.--16a,1 7 a-M ethylenea-H ydroxy-6 fl-Fluoropregnane-3,20-Di0ne (XVII) Following the procedure of Example 14, but substituting 16a,17a-methylene 618 fluoro-3 3,5a-dihydroxypregnan-20-one (XVI) (from Example 28) as starting material, yields crystalline 16a,17a-methylene-5oc-hydroxy-6 3- fluoro-pregnane-3,20-dione (XVII).

Example 31.16a,17a Methylene-5a-Hydr0xy-6fi-Chl0 r0pregnane-3,20-Di0ne (XVII) Following the procedure of Example 15, but substituting l6a,17a-methylene 6 3 fluoro-3/3,5a-dihydroxypregnan-ZO-one (XVI) (from Example 29) as starting material, yields light-colored, crystalline 16a,17a-methylene- 5a-hydroxy-6 9-chloropregnane-3,20-dione (XVII).

Example 32 .160c,1 7a-Metlzylene-6/3-Fla0r0-4-Pregnene- 3,20-Di0rze and 16a,1 7 a-Methylene-6a-F lu0ro-4-Pregnene-3,20-Di0ne (1 6a,] 7a-Methylene-fifi-Fluoroprogesterone and 1 6a,] 7 a-M ethylene-6 a-F luoroprogesterone) Following the procedure of Example 16, but substituting 16a,17a-methylene 50c hydroxy-6fl-fiuoropregnane- 3,20-dione (XVII) (from Example 30) as starting material, yields crystalline 16a,17ot-IllCthYlCIlfi-fifi-IIUOIOPIO- gesterone (V) and l6a,l7a-methylene-6a-fluoroprogesterone'(V).

Example 33.I6a,1 7a-M ethylene-613$ luoroprogesterone Following the procedure of Example 17, but substituting l6a,l7a-methylene 5a hydroxy-6fi-fluoropregnane- 3,20-dione (XVII) (from Example 30) as starting material, yields crystalline, 16a,17a-methylene-6fi-fiuoroprogesterone (V).

Example 34.16a,1 7a-Methylene-6a-Flu0r0pr0gester0ne (V) From I 6a,] 7a-Methylene-6p-Flu0r0progester0ne Following the procedure of Example 18, but substituting 16a,17a-methylene-6fl-fluoroprogesterone (V) (from Examples 32 or 33) as stalting material, yields lightcolored crystals of 16a,l7a-methylene-6cz-fiuoroprogesterone (V).

Example 35 .1 6a,] 7a-M ethylene-6 a-Chl0r0-4-Pregnene- 3,20-Di0ne (I6a,I7a-Methylerze 6a Chloroprogesterone (V) Following the procedure of Example 19, but substituting 16a,l7a-methylene 5a hydroxy-6fi-chloropregnane- 3,20-dione (XVII) (from Example 31) as starting material, yields pure 16a,17a-methylene-6a-ehloroprogesterone (V).

Example 36. 1604,]7a-Methylene-4,6-Pregnadiene-3,20- Dione (l6a,l7a-Methylene 6 Dehydroprogesterone) (XVIII) A solution of 12 g. of l6a,l7a-methylene-4-pregnene- 3,20-dione (V) (fro-m Example 4A) and 10 g. of chloranil in 500 ml. of tertiary amyl alcohol is refluxed for a period of about 4.5 hours. The tertiary amyl alcohol is then distilled under vacuum in a nitrogen atmosphere. The residue is dissolved in methylene chloride and then shaken with dilute sodium hydroxide. The precipitate that forms is separated by filtration through diatomaceous earth. The organic phase of the filtrate is separated and washed with dilute sodium hydroxide, water and then dried. The solvent is distilled leaving a residue (crude and crystalline) which after purification by chromatography through a Florisil column and crystallization gives l6a,17a-methy1ene-4,6-pregnacliene-3,20-dione (XVIII).

Example 37.-16a,1 7a-Methylene-6-Methyl-4,6 Pregnadiene-3,20-Di0ne (16a,1 7a-Methylene-6-Methyl-6 Delzydroprogesterone) (XVIII) Following the procedure of Example 36, but substituting 16a,17a-methylene-6a-methyl-4-pregnene-3,20 dione (V) (from Example 4) as starting material, yields light-colored crystalline, 16a,17a-methylene-6-methyl-4,6-pregnadiene- 3,20-dione (XVIII).

Example 38.-16a,17a-Methylene-6-Fla0ro 4,6 Pregnadz'ene3,20-Di0ne (16cc,] 7 a-M ethylene-6a-F lu0r0-6-Dehydroprogesterone) (X VIII) Following the procedure of Example 36, but substituting 16a,l7a-methylene-6a-fiuoro-4-pregnene-3,20 dione (V) (from Example 22) as starting material, adding 20 g. of calcium carbonate to the reaction mixture and refluxing it for about 24 hours in an oxygen-free atmosphere, yields light-colored crystalline, 16a,17a-methylene-6-fiuoro-4,6- pregnadiene-3,20-dione (XVIII).

Example 39.I6a,17a-Methylene-6-Flaoro 4,6 Pregnadiene-3,20-Di0ne (I 604,] 7a-Methylene-6-Flu0r0-6 Dehydroprogesterone) (XVIII) Following the procedure of Example 38, but substituting 16a,17a-methylene-6fi-fiuoro-4-pregnene-3,20 dione (V) (from Example 22) as starting material, yields crystalline l6a,l7a-met-hylene'6-fiuoro-4,6-prcgnadiene 3,20 dione (XVIII).

dierte-3,20-Dine (16a,]7a-Methylene-6-Chl0r0-6 Dehytlroprogesterone) (X VH1 Following the procedure of Example 36, but substituting 16a,17m-n1ethylene-6oechloro-4-pregnene-3,20 dione (V) Example 41 .16ot,17a-Metltylene-1,4-Pregnadiene 3,20-

Dione (16 70c Methylene 1 Dehydroprogesterone) (XXI) A mixture containing 10 g. of 16u,17a-n1ethylene-4- pregnene-3,20-dione (V) (from Example 4A), 500 ml. of tertiary butyl alcohol, 5 ml. of glacial acetic acidand 4 g. of selenium dioxide is warmed at refiux for a period of about 24 hours. An additional 4 g. portion of selenium dioxide is added and warming is continued for another 24 hour period.

The reaction mixture is cooled and filtered. The filtrate is concentrated to about 150 ml., then slowly diluted with 850 ml. of water. The resulting precipitate is isolated by filtration. The precipitate is dissolved in 300 ml. of ethyl acetate, then Washed successively with hour 100 ml. portions of freshly prepared cold ammonium sulfide, dilute ammonium hydroxide, water, dilute hydrochloric acid and water. The solution is dried over sodium sulfate and evaporated to give a residue containing l6a,l7otmethylene-1,4-pregnadiene-3,ZO-dione (XXI) The residue is dissolved in 50 ml. of methylene chloride and 100 ml. of Skellysolve B. The solution is then chromatographed over a column containing 400 g. of Florisil. The column is eluted with Skellysolve B containing increasing proportions of acetone to give 16a,17urnethylene-1,4-pregnadiene 3,ZO-dione (XXI), a light colored, crystalline solid, which can be further purified by recrystallization from acetone-Skellysolve B mixtures.

Heating 16e,l7e-methylene-4-prcgnene-3,ZO-dione (V) v in dry benzene with 2,3-dichloro-5,6-dicyanobenzoquinone under refiuxfor a period of about 12 hours (as in British Patent 852,847) also yields l6a,17 x-methylene-1,4-pregnadiene-LZO-dione (XXI).

Example 42.16a,]7a-Methylene-6ot-Methyl-l,4 Pregnadiam-3,2 (l -dione (1 6 0a,] 7 a-M ethy lens-6 a-M ethyl-1 Dehydroprogesterone) (XXI) Following the procedure of Example 41, but substituting 16a,l7ot-methylene-6u-methyl-4-pregnene-3,20 dione (V) (from Example 4) as starting material, yields light colored crystalline, Ma na-methylene 6oz methylene 6ozmethyl-l,4-pregnadiene-3,ZO-dione (XXI).

Example 43 .1 6 ot,1 7oc-Methylene-6u-Flu0ro-1 ,4 Pregnadlene-3,20-Dione (16 7a-Methylene-6ct-FlMoro-1-Dehydroprogesterone) (XXI) 16a,17oemethylene-6a-fiuoro-l,4 pregnadiene-3,20 dione Example 45.16a,1 7a-Methylene-6a-Chlore-1,4 Pregnndiene-3,20-Di0ne (16a,]7e-Methylene-6a-Chloro-1-Dehydroprogeslerone) (XXZ) Following the procedure ofi Example 41, but substituting 16a,17a-methylene-6a-chloro-4-pregnene-3JO dione (V) lated by filtration.

(from Example 23) as starting material, yields pure crystalline 160i,17a-methylene-6e-chloro-l,4-pregnadiene-3,20'- dione (XXI).

Example 46. 16o:,17d Methylene 1,4,6 Pregnatriene- 3,20-Dione (16 7a-M ethylene-1 ,6 Bisdehydroprogesterone) (XX) A mixture containing 10 g. of 16a,l7oc-methylene-4,6- pregnadiene-3,20-dione (XVIII) (from Example 36), 500 ml. of tertiary butyl alcohol, 5 ml. of glacial acetic acid and 4 g. of selenium dioxide is warmed at reflux for 24 hours. An additional 4 g. portion of selenium dioxide is added and warming is continued for another 24-hour period.

The reaction mixture .is cooled and filtered. The filtrate is concentrated to about 150 ml., then slowly diluted with 850 ml. of water. The resulting precipitate is iso- The precipitate is dissolved in 300 ml; ofethyl acetate, then washed with four lOO-ml. portions of freshly prepared cold ammonium sulfide, dilute ammonium hydroxide, water, dilute hydrochloric acid and water. The solution is dried over sodium sulfate and evaporated to give a residue containing 16a,l7u-methylone-1,4,6-pregnatriene-3,ZO-dione (XX).

, The residue is dissolved in 50 ml. of methylene chloride and 100 ml. of Skellysolve'B hexanes. The solution is then chromatographed over a column containing 400 g. of Florisil. The column is eluted with increasing proportions of acetone in Skellysolve B hexanes to give 16a,l7a-methylene-l,4,6-pregnatriene-3,ZO-dione (XX), a

crystalline solid, which canbe further purified by recrystallization from acetone-Skellysolve B hexanes mixtures.

Example 47.-]6a,17u-Methylene 6 Methyl-1,4,6-Pregndtrz'ene-3,20Dione (160:,170: Methylene-6a-Methyl- 1,6-Bisa'ehydroprogeslerone) (XX) Following the procedure of Example 46, but substituting 16a,17oc methylene-6-methyl4,6-pregnadiene-3,20-dione (XVHI) (from Example 37) as starting material, yields pure, crystalline 160 17 methylene-6-methyl-1,4,6-pregnatriene-3,20-dione (XX).

Example 48.] 6a,] 7a-M ethylene 6 Fluor0-1,4,6-Pregnatrz'ene-3,20-Di0ne (16a,17u-Methylene 6a Fluore- J ,6-Bisdehydroprogesterone) (XX) Following the procedure of Example 46, but substituting l6e,l7ec methylene *6 fiuoro-4,6-pregnadiene-3,20-

dione (XVIII) (fromExample 38) as starting material,

yields light colored, crystalline, 1600,1704 methylene 6- lluoro-l,4,6-pregnatriene 3,ZO-dione (XX).

Example 49.16x,17e-Methylene t6 Chl0ro-1,4,6-Preg natrz'ene-3,20-Di0ne (16a,]7a-Metlzylene-6-Chloro-1,6-

Bisdelzydroprogesterone) (XX) Following the procedure of Example 46, but substituting 16C(,17Ct methylene-6-chloro-4,6-pregnadiene-3,20-dione (XVIIE) (from Example 40) as starting material, yields crystalline 16a,17oz-methylene-6 chloro-1,4,6-pregnatriene- 3,20-dione (XX).

Example 50.---] 6a,] 7oz-Methylene-1,4,6-Pregnatriene-3,20-

Dione (16a,17ot Methylene 1,6 Bisdehydroprages terone) (XX) A solution of 12 g. of 16a,l7a-methylene-l,4-pregnadiene-.3,20-dione (XXI) (from Example 41) and 10 g. of chloranil in 500 ml. of tertiary amyl alcohol is re iluxed for a period of about4.5 hours. The tertiary amyl alcohol is then distilled off under vacuum in a nitrogen atmosphere. The residue is dissolved in methylene chloride and then shaken with dilute sodium hydroxide. The

precipitate that forms is separated by filtration through diatomaceous earth. The organic phase of the filtrate is separated, washed first with dilute sodium hydroxide solution, then water and dried. The solvent is distilled off 23 leaving a residue of crystalline l6a,17u-methylene-1,4,6- pregnatriene-3,20-dione (XX).

Example 51.--] 6 a,] 7a Methylene-6-Methyl-1,4,6-Pregnatriene-3,20-Dione (1 6a,] 7 oc-M ethyl ene-6 -M ethyl-I ,6- Bisdehydroprogesterone) (XX) Following the procedure of Example 50, but substituting 16a,17e methylene-Ga-methyl-1,4-pregnadiene-3,20- dione (XXI) (from Example 42) as starting material, yields crystalline 16oz,l7oi-methylene-6-methyl-1,4,6-pregnatriene-3,20-dione (XX).

Example 52.160t,17ot Metlzylene-6-Fluor0-1,4,6-Pregnatrz'ene-3,20-Di0ne (160a,]7a-Methylene-6-Flu0r0-I,6- Bisdelzydroprogesterone (XX) Following the procedure of Example 50, but substituting l6a,l7a-methylene 6oz fluoro-1,4-pregnadiene-3,20- dione (XXI) (from Example 43) as starting material, yields crystalline 16a,17e-methylene-6-fiuoro-1,4,6-pregnatriene-3,20-dione (XX).

Example 53.-16a,1 7u-Methylene-6-Flu0r0-I ,4,6-Pregnatriene-3,20-Di0ne (16e,I7a-Methylene 6 Flu0r0-1,6- Bisdehydroprogesterone) (XX) Following the procedure of Example 50, but substituting 160:,l7oc-ll16ihYl6l'l6 6,8 fluoro-l,4-pregnadiene-3,20- dione (XXI) (from Example 44) as starting material, yields crystalline 16a,l7ot-n1ethylene-6-fiuoro-1,4,6-pregnatriene-3,20-dione (XX).

Example 54.--16a,]Zia-Methylene-6-Chl0ro-1,4,6-Pregnaa triene-3,20-Di0ne (160a,! 7a-Methylene 6 Chime-1,6- Bisdehydroprogesterone) (XX) Following the procedure of Example 50, but substituting 16a,17u-methylene6a-cl1loro 1,4 pregnadiene-3,20- dione (XXI) (from Example 45) as starting material, yields light colored, crystalline 160:,170: methylene 6- chloro-1,4,6-pregnatriene-3,20-dione (XX).

Example 55.16a,17a Methylene-11 ot-Hydr0xy-4-Pregnene-3,2O-Di0ne (16a,1 7a-Methylene-I I a-Hydroxyprogesterone) (XIX) A medium is prepared containing g. of Cerelose dextrose technical grade and 20 g. of corn steep liquor (60% solids) in sufficient tap water to make up one liter of solution. One hundred liters of such a medium is adjusted by the addition of 25 percent sodium hydroxide solution to a pH of 5. Thereto is then added 400 ml. of lard oil and lard-oil octadecanol as an anti-foaming agent. This medium is sterilized for 45 minutes at 20 lbs. pressure and inoculated with Rhizopus nigricans minus strain, American Type Culture Collection No. 6227b, and incubated for 24 hours at a temperature of 28 C. using a rate of aeration and stirring such that the oxygen uptake is 6.3 to seven millimoles per hour per ml. of sodium sulfite according to the method of Cooper, Fernstrom and Miller, Ind. Eng. Chem. 36,504 (1944). To this medium containing a 24 hour growth of Rhizopus nigricans minus strain is added 6 g. of 16a,l7a-methylene-4-pregnene- 3,20-dione (V) (from Example 4A) in 150 milliliters of acetone to provide a suspension of the steroid in the culture. After an additional 24 hour period of incubation under the same conditions of temperature and aeration, the beer and mycelium are extracted. The mycelium is filtered, washed twice each time with a volume of acetone approximately equal to the volume of the mycelium, and extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the myceliurn. The acetone and methylene chloride extracts including solvents are added to the beer filtrate. The mixed extracts and beer filtrate are extracted successively with two one-half by volume portions of methylene chloride and then with two one-fourth by volume portions of methylene chloride. The combined methylene chloride extracts are washed with two one-tenth by volume portions of a two percent aqueous solution of sodium bicarbonate and then with two one-tenth by volume portions of water. After drying the methylene chloride extracts with about three to five grams of anhydrous sodium sulfate per liter of solvent and filtering, the solvent is removed by distillation. The residue is dissolved in a minimum of methylene chloride and chromatographed over Florisil. The product, eluted with increasing proportions of acetone in Skellysolve B, is recrystallized from methanol to yield light colored, crystalline 16a,17a-methylene-l la-hydroxy-4-pregnene-3,20-dione (XIX) Example 56.-16oc,17oc Methylene 11a Hydr0xy-6a- Methyl-4-Pregnene-3,20-Dione (16,17a Methylene- 1Ia-Hydr0xy-6a-Methylprogesterone) (XIX) Following the procedure of Example 55, but substituting 1606,1706 methylene-6e-methyl-4-pregnene-3,20-dione (V) (from Example 4) as starting material, yields crystalline l6a,l7ot methylene-1 1ot-hydroxy-a-methyl-4-pregnene-3,20-dione (XIX).

Example 5 7.-I 6a,] 7 or M ethylene-I I a-H ydr0xy-6 ac-F luoro-4-Pregnene-3,20-Di0ne (16ot,17oc Methylene-11a- Hydroxy-6a-Flu0r0progester0ne) (XIX) Following the procedure of Example 55, but substituting l6a,l7a methylene-6a-fluoro-4-pregnene-3,20-dione (V) (from Example 22) as starting material, yields light colored crystals of 1606,170c-fl'll6ll1Yl6116-110t-hydIOXy-6mfiuoro-4-pregnene-3,ZO-dione (XIX).

Example 58.---16oc,1 7a M ethylene-1 I a-H ydr0xy-6B-F luoro-4-Pregnene-3,20-Dione (1611,] 7a M ethylene-1 1 a- H ydroxy-tifl-F laoroprogesterone) (XIX) Following the procedure of Example 55, but substituting 16a,l7 x methylene-6,8-fiuoro-4-pregnene-3,ZO-dione (V) (from Example 22) as starting material, yields crystalline 16a,17a-methylcne-l loc-hydroxy 6fi-fluoro-4-pregnene-3,20-dione (XIX).

Example 59.-16a,17a Methylene 11cc Hydroxy 60- Chl0ro-4-Pregnene-3,20 Dione (16a,17a M ethylene- 11 a-Hydr0xy-6a-ChIoroprogesterone) (XIX) Following the procedure of Example 55, but substituting l6e,l7a methylene-6a-chloro-4-pregnene-3,ZO-dione (V) (from Example 23) as starting material, yields crystalline 16a, 17a-methylene-l let-hydroxy-6a-chloro-4-pregnene-3,20-dione (XIX).

Example 60.--1 604,71 a-M ethylene 4 Pregame-3,11,20- Trione (I6a,17a Methylene II Ketoprogesterone) (XIXa) A solution is prepared containing 3.5 g. of 160:,l7ocmethylene-1la-hydroxyprogesterone (XIX) (from Example 55) in 50 ml. of acetic acid at room temperature. Thereto is added dropwise a solution of 2 g. of chromium trioxide in 50 ml. of acetic acid and 0.5 ml. of water. During the addition, the temperature is maintained between 20 to 23 C. and thereafter for another period of 1.5 hours. The reaction mixture is then diluted with 1 l. of water and extracted with six -milliliter portions of methylene chloride. The extracts are combined, washed with dilute sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The thus obtained solid is recrystallized from methanol to yield light colored, crystalline, :,17a methylene 4 pregnene-3,11,20-trione (XIXa).

Example 61 .--16oc,1 7a-Methylene-6oi-Methyl-4-Pregnene- 3,11,20 Trione (160:,170: Methylene 6u-Methyl-1I- Ketoprogesterone) (XIXa) Following the procedure of Example 60, but substituting l6a,17a methylene 11u-hydroxy-6a-methyl-4-pregnene-3,20-dione (XIX) (from Example 57) as starting material, crystalline l6e,l7a-methylene'Ga-rnethyll-pregnene-3,11,20-trione (XlXa).

. 25 Example 62.16a,17a Methylene 6o: F lzwr-4-Pregnene-3,1l,20-Trione (1666,170l-Melhylll-6t!-FlllOlO-1 1- Ketqprogesterone) (X 1 X n Following the procedure of Example 60, but substituting 16a, 17a-methylene-l 1 whydroxy-6a-fluoro-4-pregnene- 3,20-dione (XIX) (from Example 58) as starting material, yields pure, crystalline 16a,l7a-rnethylene-6-aiuoro- 4-pregnene-3,-l 1,20-trione (XIXa) Example 63.-16ot,17a-Methylene-6fi-Fln0r0-4-Pregnene- 3,11,20 Trz'one (16a,17a Methylene 6/8-Fln0r0-1 J Ketoprogesterone) (XlXa) Following the procedure of Example 60, but substituting l6a,17u methylene 11a -'hydroxy-6B-fluoro-4-pregnene-3,20-dione (XIX) (from Example 59) as starting material, yields crystalline, 16a,17ot-rnethylene-6fl-fluoro- 4-pregnene-3,1 1,20-trione (XIXa) Example 64 .1 6 (1,1 7a-Methylene-6et-Chl0r0-4-Pregnene- 3,11,20 Trione (16a,17a Methylene 6 Ot-ChlOlO-Z 1 Ketoprogesterone) (XIX a) a Following the procedure of Example 60, but substituting 16,17ot methylene 11why-(1rOXY-Goc-ChlOIO-4-pl6gnene-3,20-dione (XIX) (from Example 59) as starting material, yields crystalline l6oz,l'l'otll'lfilhflflIlB-fiOt-ChlOlO- 4-pregnene-3, l 1,20-trione (-XlXa) Example 65 6 0a,] 7 Ot-M ethylene-1 1 a-Hydr0xy-4,6-Pregnadiene-3,20-Di0ne (16ml 7a-Methylene-1 1 a-Hydroxy- 6-D ehydro progesterone) (XIX) Following the procedure of Example 55, but substituting l6rx,l7ot methylene 4,6 pregnadiene 3,20 dione (XVIII) (from Example 36) as starting material, yields crystalline 160a, 170a methylene-.11a-hydroxy-4,6-pregnadiene-3,20-dione (XIX).

Example 66.-t-16ot,17ot- Methylene 11a Hydroxy 6 M ethyl-4,6-Pregnadiene-3,20-Dione (160:,170: M ethylene 11oz Hydroxy-6-Methyl-6-Dehydroprogesterone) (XIX) Following the procedure of Example 55, but substituting 16ix,17oc methylene 6 methyl 4,6 pregnadiene-S,20- dione (XVIII) (from Example 37) as starting material, yields pure, crystalline l6a,l7u-methylene-1lot-hydroxy- 6-methyl-4,6-pregnadiene-3,20-dione (XIX).

Example '67.16a,17ot-Methylene-1lw-Hydroxy-ti-Flnoro- 4,6-Pregnadiene-3,20-Dione (16n,17ot M ethylene-1 1 o:- H ydr0xy-6-Fluoro-6-Dehydroprogesterone) (XIX) Following the procedure of Example 55, but substituting 16a,l7ca methylene 6-methyl-4,6-pregnadiene-3,20- dione (XVIII) (from Example 38) as starting material, yields light colored, crystalline l6a,l7ot-methy-lene-llahydroxy-6-fluoro-4,6-pregnadiene-3,20-dione (XIX).

Example 68.16ot,17oc Methylene 11a Hydroxy-6- Chlore-4,6-Pregnttdiene-3J0-Dione (16a,]7a Methylene 11a H ydroxy 6-Chl0-r0-6-Dehydroprogesterone) (XIX) Following the procedure of Example 55, but substituting 160t,170t methylene 6-ch-loro-4,6-pregnadiene-3,20- dione (XVIII) (from Example 40) as starting material,

yield-s crystalline 16oc,170t methylene l1a-hydroxy-6- chloro-4,6-pregnadiene-3,20-dione (XIX).

Example 69. 160:,170: Methylene 4,6 Pregnazliene 3,11,20-Tri0ne (XIXa) 16a,]7ct-Methylene-6-Methyl- 4,6-Pregnadiene-3,11,ZO-Trione (XIXa), 1606,170t-M2thylene-6-Flu0ro-4,6-Pregnethane-3,11,20-trione (XIX a) and 16e,17'd Methylene Chloro 4,6 Pregnadiene- 3,11,20-Tri0ne (XIXa) Following the procedure of Example 60, but substituting as starting materials, 16 oc,17a:-methyl6n6-llot-hYdlOXY- '4,6-pregnadiene-3,20-dione (XIX) (from Example 66),

diene-3,20-dione (XIX) (from Example 67), l6u,l7a-

methylene 11m hydroxy 6 fiuoro-4,6-pregnadiene 3,20-dione (XIX) (from Example 68), and 1604,17- methylene lla -hydroxy 6 chloro 4,6-pregnadiene- 3,20-dione (XIX) (from Example 70), yields, respectively, light colored, crystalline, l6a,l7a-methylen'e-4,6- pregnadiene-3,l1,20-trlone (XIXn), Ma na-methylene- 6-methyl-4,6-pregnadiene-3,l1,20-trione (XIXa), 16oz,- 17amethylene-6-fiuoro-4,G-pregnadiene 3,11,20 trione (XIXa) and 16a,l7oc-methylene-6-chloro-4,G-pregnadiene- 3,11,20-trione (XiXa).

Example ,70.16oc,17a-Methylene-11a-HydrOxy-JA-Pregnadiene-3,20-Di0ne (16 7ot-Methylene-11 a-Hytlroxyl -Dehydroprogester0ne) (XIX) Following the procedure of Example 55, but substituting l6a,l7a-methylene-l,4-pregnadiene-3,20adione (XXI) (fro-m" Example 41) as starting material, yields pure, crystalline, 17a methylene-1la-hydroxy-lA-pregnadicne-3,20-dione (XIX).

Alternatively, 160:,17a methylene-l la-hydroxyl-preg nene-3,2G-dione prepared by the method of Example 55, can be l-dehydrogenated by the method of Example 41 to give 16u,17e-rnethylene-11a-hydroxy-1,4-pregnadiene- 3,20-dione (XIX).

Example 71.-16Ct,17ct ethylene 11a Hydroxy 66t- M ethyl-1 ,4 -Pregnadiene-3,2 Q-Dione (1611,] 70c M ethylene-1 1 0e Hydroxy 6ct-Methyl-1-D ehydroprogesterone) (XIX) Following the procedure of Example 55, but substituting 16,l7a methylene-6o -methyl-1,4-pregnadiene-3,ZO-dione (XXI) (from Example 42) as starting material, yields crystalline 16a,17a-methylene-lla hydroxy-6a-methyl-1,4- pregnadiene-3,20-dione (XIX).

Alternatively, 1604,170: methylene 11cc hydroxy-umethyl-4*pregnene-3,ZO-dione, prepared by the method of Example 56, can he l-dehydrogenated by the method of'Example 41 to give 16a,17u-methylene-llot-hydroxy- 6oc-methyl1,4-pregnadiene-3,20-dione (XIX).

Example 72 .-1 6 ct,] 7o:-M ethyl ene-l 1 oz-Hydr0xy-6oz-Fluare I,4-Pregnadiene-3,20-Dione (16a,17a-Methylene- 11 ct-Hydr0xy-6a-Fln0r0-1-Dehydr0pr0gesterone) (XIX) Following the procedure of Example 55,.but'substituting 160:,17oc methylene 6a fluoro-1,4-pregnadiene-3,20-t

dione (XXI) (from Example 43) as starting material, yields crystalline, l6ot,l7a-methylene-llot-hydroxy-6otfi-uoro-l,4-pregnadiene-3,ZO-dione (XIX).

Example 7s.- 16a,17 Methylene-J1a-Hy1dr0xy-6B-Fluoro 1,4-Pregnndiene-3,20-Dione (16a,17a-Methylene- 11a H ydroxy 6,8 Flnoro 1 Dehydroprogesterone) (XIX) Example 75.--16u,17ot Methylene-1,4-Pregnadiene-3J1,

ZO-Trione (XIX a), 1 6a,] 7a-Methylene-6ot-Methyl-1 ,4- Pregne'aiene-SJ 1 ,ZO-Trione X I X a 1 6 11,1 7a-Methyl- 6716-666-Flll070-1 ,4-Pregnndiene-3 ,1 1 ,ZO-Trione XIX a) Following'the procedure of Example 60, but substituting as starting materials, 16a,17a-methylene-1lot-hydroxy- 1,4-pregnadiene-3,20-dione (XIX) (from Example 70), 16a,l7a methylene 11oz hydroxy 60c methyl 1,4- pregnadiene-3,20-dione (XIX) (from Example 71), 16a, 17a methylene 11a hydroxy 6oz fluoro 1,4 pregnadiene-3,20-dione (XIX) (from Example 72), 16a,17otmethylene 110a hydroxy 6 3 fluoro 1,4 pregnadiene- 3,20-dione (XIX) (from Example 73) and 16oc,17amethylene 11a hydroxy 60c chloro 1,4 pregnadiene-3,20-dione (XIX) (from Example 74), yields, respectively, light colored, crystalline, 16a,17 x-methylene- 1,4-pregnadiene-3,11,20-trione (XIXa), 16a,17a-methy1- ene 6a methyl 1,4 pregnadiene 3,11,20 trione (XIXa), 16a,l7ocmethylene-6a-fluoro-1,4-pregnadiene- 3,11,20-trione (XIXa), 16oz,l70t-Il'16ihYlfiIlB-6l3-fll10l0-1,4- pregnadiene-3,l1,20-trione (XIXa) and 16a,17a-methylene 6a chloro 1,4 pregnadiene 3,11,20 trione (XIXa).

Example 76.--16a,17ot Methylene 11a Hydrxy-1,4,6- Pregnatriene 3,20-Di0ne (16a,17a-Methylene-11a-Hydroxy-I ,6-Bisdehydroprogester0ne) (XIX) Following the procedure of Example 55, but substituting 16a,l7a-methylene-1,4,6-pregnatriene-3,20-dione (XX) (from Example 46) as starting material, yields crystalline l6a,17 x methylene-11a-hydroxy-1,4,6-pregnatriene-3,20-dione (XIX).

Alternatively, 160:,1704 methylene 11a hydroxy 4, 6-pregnadiene-3,20-dione, prepared by the method of Example 55, can be l-dehydrogenated by the method of Example 41, to give 16a,l7o-methylene-l1a-hydroxy-1,4, 6-pregnatriene-3,20-dione (XIX).

Example 7 7.] '6 0a,] 7 (Z-M ethylene-1 1 a-Hydr0xy-6-Methyl- 1,4,6 Pregnatriene 3*,20 Dione (16a,17a-Methylene- 11a H ydroxy 6-Methyl-1,6-Bisdehydroprogesterone) (XIX) Following the procedure of Example 55, but substituting 16a,17ot methylene 6 methyl 1,4,6 pregnatriene 3, 20-dione (XX) (from Example 47) as starting material, yields light colored, crystalline, 16a,17a-methylene-11aihydroxy-6-methyl-1,4,6-pregnatriene-3,20-dione (XIX).

Example 78.-16a,17u-Methylene-1lot-Hydroxy-o-Fluora- J ,4,6-Pregnatriene-3,ZO-Dione (160:,1 7a-Methylene-11a- Hydroxy-6-Fluor0-1,6-Bisalehydroprogesterone) (XIX) Following the procedure of Exam-pleS but substituting 16a,17a methylene 6 fluoro 1,4,6 pregnatriene 3, 20-dione (XX) (from Example 48) as starting material, yields crystalline 16a,17a-methylene-1 1a-hydroxy-6-fluoro- 1,4,6-pregnatriene-3,20-dione (XIX).

Example 79.-16OC,17C4-Mfl1ylnE-11 a-Hydroxy-ti-Chloro- J ,4,6-Pregnatriene-3,20-Di0ne (1 6 00,1 7oc-Methylene-I1ot- H ydr0xy-6-Chl0r0-1 ,6 -Bisdehydroprogesterone) (XIX) Following the procedure of Example 55, but substituting 160:,17a methylene 6 chloro 1,4,6 pregnatriene 3, 20-dione (XX) (from Example 49) as starting material, yields pure, crystalline 16a,17a-methylene-1lot-hydroxy-fichloro-1,4,6-pregnatriene-3,20-dione (XIX).

Example 80.] 6 12,1 70: M ethylene-1 ,4,6-Pregnatriene-3 11,20-Tri0ne (XIXa) 16:1,] Zia-Methylene 6 .Methyl- 1,4,6-Pregnatriene 3,11,20 Trz'one (XlXa), 161x170:- M ethylene-6-F luoro 1,4,6 Pregnatriene-3,1I,ZO-Trione (XIXa), and 16a,17a Methylene-6-Chl0r0-1,4,6- Pregnatriene-3,11,20-Tri0ne (XIXa) Following the procedure of Example 60, but substituting as starting materials, 16a,17a-methylene-1lot-hydroxy-1,4,6-pregnatriene-3,ZO-dione (XIX) (from Example 76), 1'6a,*17a-methylene 11cc hydroxy-6-methyl- 1,4,6-pregnatriene-3,20-dione (XIX) (from Example 77), 16a,17a methylene-1 lu-hydroxy 6 fluoro l,4,6- pregnatriene-3,20-dione (XIX) (from Example 78), and 1611,1711 methylene-11a-hydroxy-6-chloro 1,4,6 pregnatriene-3,20-dione (XIX) (from Example 79), yields, respectively, light colored, crystalline, 16a,17a-methylene-'l,4,6-pregnatriene-3,11,20-tri0ne (XIXa), 1611,1711- methylene-6-methyl-1,4,6-pregnatriene 3,11,20 trione (XIXa), 16a,l7a methylene-6-luoro-1,4,6-pregnatriene- 3,11,20-trione (XIXa), and l6a,l7a-rnethylene-6-chloro- 1,4,6-pregnatriene-3,11,20-trione (XIXa).

Example 81 16a,]7a-Methylene-I1fl-Hydr0xy-4-Pregnene-3,20-Di0ne (16a,17tx-Methylene Hydroxyprogesterone) (XIX) A seed culture of Curzninghamella blakesleeana (ATCC 8688b), obtained from spores grown on a 2% agar, 5% malt extract solids at a pH of 6.0 is prepared by growth in a medium containing, per liter of tap water, 10 g. of dextrose (Cerelose) and 20 g. of liquid corn steep liquor (containing about 1.2 g. solids) adjusted to a pH of about 5 with 25% aqueous sodium hydroxide.

Five one-liter portions of the above medium are inoculated with the seed culture and growth with aeration and shaking was continued for 48 hours. Then 0.2 g. of 16a,17ot-methylene-4pregnene-3,20-dione (V) (from Example 4A) in 30 ml. of alcohol is added to each flask and fermentation continued for another 48 hours, at which time the pH is 5.9.

The mycelium is filtered from the beer and the beer extracted four times with one-fourth by volume amounts of methylene chloride containing 25% ethyl acetate. The extracts are evaporated to dryness. The residue thus obtained is redissolved in ml. of methylene chloride and chromatographed on a column of magnesium silicate. The column is developed with hexanes containing increasing proportions of acetone to elute a mixture containing the desired 11/3-hydroxy-product. The crude product is crystallized from a mixture of hexanes and acetone and recrystallized from the same solvent pair to yield light colored, crystalline 16a,17a-methylene-1lp-hydroxy-4-pregnene-3,20-dione (XIX).

Example 82.16a,17a Methylene 11p Hydroxy 60:- M ethyl-4-Pregnene 3,20 Dione (16a,17a-Methylene- 11fi-Hydroxy-6ot-Methylpr0gester0ne) (XIX) Following the procedure of Example 81, but substituting 160.,17a methylene-6oc-methyl-4-prcgnene-3,20-dione (V) (from Example 4) as starting material yields crystalline 16a,l7a-methylene-1 lfl-hydroxy-6a-methyl-4-pregnene-3,20-dione (XIX).

Example 83.-16a,17a Methylene 11p Hydroxy 6a- Fluoro 4 Pregnene-3,20-Di0ne (I6u,17u-Methylene- I1,B-Hydroxy-6a-Flu0r0pr0gester0ne) (XIX) Following the procedure of Example 81, but substitutin g 16a,17wmethylene-6a-fiuoro-4-pregnene 3,20 dione (V) (from Example 22) as starting material, yields pure, crystalline 16e,17a-methylene-1lp-hydroxy 6a fluoro-4- pregnene-3,20-dione (XIX).

Example 84.16ot,17a Methylene 11B Hydroxy 6,6- F luoro-4- regnene 3,20 Dione (16a,17u-Methylene- I1p-Hydroxy-tifi-Flnoroprogesterone) (XIX) Following the procedure of Example 81, but substituting l6a,17a-methylene-6fi-fluoro-4-pregnene 3,20 dione (V) (from Example 22) as starting material, yields light colored, crystalline 16a,17et-methylene-11p-hydroxy-6B- fiuoro-4-pregnene-3,20-dione (XIX).

Example 85.-16e,17a Methylene 11p Hydroxy 6a- Chl0r0-4-Pregnene 3,20 Dione (16a,17a-Methylene- I I p-H ydr0xy-6a-Chloroprogesterone) (XIX) Following the procedure of Example 81, but substituting l6a,l7a methylene-6a-chloro-4-pregnene-3,20-dione (V) (from Example 23) as starting material, yields crystalline l6a,17a-methylene-1lfl-hydroxy-6a-chloro-4-pregnene-3,20-dionc (XIX).

Example 86.-16a,17a-1\ 1ethylene 4 Pregnene-3,11,20-

T rione (161,170; Methylene 11 Ketoprogesterone) (XZXa) Following the procedure of Example 60, but substituting 16u,17ot-methylene-1lfl-hydroxy 4 pregnene 3,20- dione (XIX) (from Example 81) as starting material, yields pure, crystalline 16a,l7o -methylene-4-pregnene-3, 11,20-trione (XIXa).

Example 87.-16a,1 7a-Methylene-6u-1l Iethyl-4-Pregnene- 3,11,20-Trione (16a,17a Methylene 60c Methyl 11- Ketoprogesterone) (XIXa) Following the procedure of Example 60, but substituting 161x, l7a-methylene-1 l fi-hydroxy 6a methyl-4-pregnene-3,20-dione (XIX) (from Example 82) as starting material, yields crystalline 16a,17a-methylene-6a-methyl- 4-pregnene-3,l1,20-trione (XIXa) Example 88.] 6 05,1 7 Oc-M ethylene-6 a-Fluor-4-Pregnene- 3,11,20-Tri0ne (160:,17a Methylene 6oz Fluoro 11- Ketoprogesterone) (XIXa) Following the procedure of'Example 6'0, but substituting 160:,170: methylene-1 lfi-hydroxy 6oz fiuoro-4-pregnene-3,20-dione (XIX) (from Example 83) as starting material, yields pure, crystalline 16a,l7a-methy1ene-6aflnoro-4-pregnene-3,l 1,20-trione (XIXa) Example 89.-16a,]7ot-Methylene-6,8-Flu0r0-4-Pregnene- 3,11,20-Tri0ne (160:,1704 Methylene 65 Fluoro 11- Ketoprogesterone) (XIXa) Following the procedure of Example 60, but substituting 16oz,17u methylene-l le-hydroxy-6B-fluoro 4 pregnene-3,20-dione (XIX) (from Example 84) as starting material, yields crystalline 16a,l7a-methylene-6fi-fluoro- 4-pregnene-3,1 1,20-trione (XIXa) Example 90.16u,1 7a-Methylene-6a-Chl0r0-4-Pregnene- 3,11,20-Tri0ne (160:,1704 Methylene 6a Chloro 11- Ketoprogesterone) (XIXa) Following the procedure of Example 60, but substituting 16u,l7a methylene-l1,8-hydroxy-6ot-chlor0 4 pregnene-3,20-dione (XIX) (from Example 85) as starting material, yields crystalline, 16a,17e-methylene-6ot-chloro- 4-pregnene-3,l 1,20-trione (XIXa) Example 91.--16Dt,1705 Methylene 11B Hydroxy 4,6- Pregnadiene-3,20Di0ne (16a,17a M ethylene-1 1 B-H ydr0xy-6-Dehya'roprogesterone) (XIX) Following the procedure of Example 81, but substituting 16:4,17a methylene 4,6 pregnadiene 3,20 dione (XVIII) (from Example 36) as starting material, yields light colored, crystalline '16u,l7c-methylene-llfi-hydroxy-4,6-pregnadiene-3,ZO-dione (XIX).

Alternatively, 160e,17ot methylene-l 1B-hydroxy-4-pregnone-3,20-dione (XIX), prepared by the method of Example 81, can be G-dehydrogenated by the method of Example 36 to -give 16a,l7a-methylene-1l [3-hydroxy-4,6- pregnadiene-3,20-dione (XIX).

Example 92. 160a,] 7a-Mezhylene-11fl-Hydr0xy-6-Methyl-4,6-Pregnadiene 3,20 Dione (16a,17a-Methylene- 11,8 H ycli'oxy 6 Methyl 6- Dehydroprogesterone) (XIX) Example 93.-16u,17ot Methylene 11B Hydroxy 6- F lu0r0-4,6-Pregnadiene-3,20-Di0ne (16 170: M ethylene 1'15 H ydroxy 6-Flu0r0-6-Dehydroprogesterone) (XIX) Following the procedure of Example til, but substituting 16a,l7e-methylene-6 fluoro 4,6 pregnadiene 3,20-

dione (XVIII) (fromExample 38) as-starting material, yields light colored, crystalline 16e,17ot-methylene-llphydroxy-6-fiuoro-4,6-pregnadiene-3,20-dione (XIX).

Alternatively, 160:,170t methylene hydroxy 60ttluoro-4-pregnene-3,ZO-dione ()GX), prepared by the method of Example 83, can be 6-dehydrogenated by the method of Example 38 to give l6ot,l7ct-methylene-llf3- hydroxy-6-fiuoro-4,6-pregnadinene-3,20-dione (XIX).

Example 94.-16q,170t Methylene 115 Hydroxy 6- Chloro 4,6 Pregnadiene 3,20 Dione (115 170:- Methylene 115 Hydroxy 6 Chloro 6 Dehydraprdgesterone) (XIX Following the procedure of Example 81, but substituting 16a,l7 x methylene 6 chloro 4,6 pregnadiene- 3,20-dione (XVIII) (from Example 40) as starting material, yields crystalline l6ot,17a-methylene-1lfi-hydroxy-G- chloro-4,6-pregnadiene-3,ZO-dione (XIX).

Alternatively, l6a,17a methylene 11p hydroxy 60cch1oro-4-pregnene-3,ZO-dione (XIX), prepared by the method of Example 85, can be o-dehydrogenated by the method of Example 40 to give looelh-methylene-llflhydroxy-G-chloro-4,6-pregnadiene-3,20-dione (XIX).

Example 95.a,17ct Methylene 4,6 Pregnadiene- 3,11,20 Trione (XlXa), 1604,17ot ll lethylene 6- Methyl-4,6-Pregnadiene-3,11,ZO-Trione (XlXa), 16a- 1704 Methylene 6 Fluoro 4,6 Pregnadiene 3,11, ZO-Trione (XlXa), and 16a,]7ot-Methylene-6 Chl0v'0- 4,6-Pregnadiene-3,1l ,ZO-Trione (XIX a) Following the procedure of Example 60, but substituting as starting materials, l6a,l7ot-rnethylene-1lfi-hydroxy- 4,6-pregnadiene-3,20-dione (XIX) (from Example 91), 160417 methylene 11B hydroxy 6 methyl 4,6- pregnadiene-3,20-dione (XIX) (from Example 92), 160:, 1711 methylene ll {3 hydroxy 6 fluoro 4,6 pregnadiene-3,20-dione (XIX) (from Example 93), 16a,l7otmethylene 11B hydroxy 6 ehlo-ro 4,6 pregnadiene- 3,20-dione (XIX) (from Example 94), yields, respectively, light colored, crystalline 16m,I7e-methylene-4,6-pregnadiene-3,l1,20-trione (XlXa), 16ce,170c methylene-6- methy1-4,G-pregnadiene-S,11,20-trione (XIXa), 160L,17OL- methylene 6 fluoro 4,6 pregnadiene 3,11,20 trione (XlXa), and 16a,l7a-methy1ene-6-chloro-4,6-pregnadiene-3,11,20-trione (XIXa).

Example 96.160t,17ot Methylene 11B Hydroxy 1,4- Pregnadiene 3,20 Dione (1611,] 7st Methylene- 11 ti-Hydnoxy l -Dehydr0pr0gester0ne-) (XIX) Example 97.16 x,17a-Methylene 11B Hydroxy 6o:- Methyl 1,4 Pregnadiene 3,20 Dione (1604,1 70:- Methylene- 11/3 Hydroxy 6a Methyl 1 Dehydraprogesterone) (XIX) Following the procedure of Example 81, but substituting 16,l7ot methylene 6a methyl 1,4 pregnadiene-3,20- dione (XXI) (from Example 42) as starting material, yields crystalline 16a,17e-methylene-1'1,8 hydroxy 6amethyl-1,4-pre'gnadiene-3,20-dione (XIX).

31 Alternatively, 160:,170: methylene 11p hydroxy 6o:- methyl-4-pregnene-3,20-dione (XIX), prepared by the method of Example 82, can be l-dehydrogenated by the method of Example 42 to give 16a,17a-methylene-l lfl-hydroxy-6a-methyl-l,4-pregnadiene-3,20-dione (XIX).

Example 98.16a,17a Methylene 11/3 Hydroxy 6a- Fluoro 1,4 Pregnadiene 3,20 Dione (16oz,17ot Methylene JIB-Hydroxy 6a Fluoro 1 Dehyclroprogesterone) (XIX) Following the procedure of Example 81, but substituting 16a,17a-methylene-6a-fluoro-1,4pregnadiene 3,20- dione (XXI) (from Example 43) as starting material, yields crystalline l6a,l7oc-methylene 11p hydroxy 60cfiuoro-1,4-pregnadiene-3,ZO-dione (XIX).

Alternatively, 160:,170: methylene 11,8 hydroxy 6nfiuoro-4-pregnene-3,ZO-dione (XIX), prepared by the method of Example 83 can be l-dehydrogenated by the method of Example 43 to give 16u,17e-methylene-l1fihydroxy-6a-fiuoro-l,4-pregnadiene-3,20-dione (XIX).

Example 99.16oc,17ot Methylene 11 3 Hydroxy 6 3- Fluoro 1,4 Pregnadiene 3,20 Dione (1604,1704- Methylene IIfi-Hydroxy 6/3 Floaro 1 Dehydraprogesterone) (XIX) Following the procedure of Example 81, but substituting 16c:,17oc methylene 618 fiuoro 1,4 pregnadiene- 3,20 dione (XXI) (from Example 44) as starting mate rial, yields pure crystalline l6a,l7a-methylene-llfi-hydroxy-6fi-fluoro-1,4-pregnadiene-3,20-dione (XIX).

Alternatively, 16oc,17oz methylene 11B hydroxy- 6,8-flnoro-4-pregnene-3,ZO-dione (XIX), prepared by the method of Example 84, can be l-dehydrogenated by the method of Example 44 to give l6a,17a-methylene-11,8- hydroxy-GB-fluoro-l,4-pregnadiene-3,20-dine (XIX).

Example 100.'160t,170t-M[hyl6ll 11p Hydroxy 6a- ChloroJ ,4-Pregnadiene-3,20-Dione (1 601,1 7u-IJethyl' ene 11,3 Hydroxy 60c Chloro 1 Dehydr progesterone) (XIX) Following the procedure of Example 84, but substituting 16u,17a methylene 6oz chloro 1,4 pregnadiene- 3,20-dione (XXI) (from Example 45) as starting material, yields crystalline 16u,17a-methylene-11fil-hydroxy-6achloro-1,4-pregnadiene-3,20-dione (XIX).

Alternatively, 16a,17a-methylene 11/3 hydroxy 6achloro-4-pregnene-3,20-dione (XIX), prepared by the method of Example 85, can be l-dehydrogenated by the method of Example 45 to give 160:,17oc-metl1Yl6I16-1119- hydroxy-fia-ehloro-l,4-pregnadiene-3,20-dione (XIX).

Example 101 .16a,]7a-Methylene-1,4-Pregnadiene-3,11,

ZO-Trione (XIXa), 16a,17a-Methylene-6a-Methyl-1,4- Pregnadiene-3,11,20-Tri0ne (XIX a) 1611,] 7a-Methylene 6a FlllOJO 1,4 Pregnadiene 3,11,20 Trione (XIXa), 1611,]7a-Methylene-6fl-Flu0r0-1,4-Pregnaa'iene-3,11,20-Tri0ne (XIXa) and 16a,17u-Metlzylene-6a- Chloro-I,4-Pregnadiene-3,11,20-Tri0ne (XIXa) 32 Example 102. 16a,]7a-Metlzylene-IIfl-Hydr0xy-1,4,6- Pregnatriene 3,20-Di0ne 1 604,1 7 a-M ethylene 11B- Hydroxy-1,6-Bisa'ehydroprogesterone) (XIX) Following the procedure of Example 81, but substituting 16a,17 x-methylene 1,4,6-pregnatriene 3,20-dione (XX) (from Example 46) as starting material, yields crystalline 16a, l7a-methylene-1 1 fi-hydroxy-l,4,6-pregnatriene-3,20-di0ne (XIX).

Alternatively, l6a,l7e-methylene llfl-hydroxy 4,6- pregnadiene-3,20-dione (XIX) prepared by the method of Example 91, can be l-dehydrogenated by the method of Example 46 to give l6a,17a-methylene-1lit-hydroxy- 1,4,6-pregnatriene-3,20-dione (XIX).

Example 103. 1601,17 Methylene- Hydroxy Methyl-1,4,6-Pregnatriene-3,20-Dione (16a,1 7a-Methylene-Ilfl-Hydroxy 6-Methyl 1,6-Bisdehydropr0gesterone) (XIX) Following the procedure of Example 81, but substituting 16a,17a-methylene-6-methy1-1,4,6-pregnatriene-3,20- dione (XX) (from Example 47) as starting material, yields pure, crystalline 16a,l7a-methylene-llfl-hydroxy- 6-methyl-1,4,6-pregnatriene-3,20-dione (XIX).

Alternatively :,17ot-I1'16thYl6H6-1 1 B-hydroxy-6-rnethyl- 4,6-pregnadiene-3,20-dione (XIX), prepared by the method of Example 92, can be l-dehydrogenated by the method of Example 47 to give 16a,17a-methylene-llflhydroxy-fi-methyl-1,4,6-pregnatriene-3,20-dione (XIX).

Example 104. 160:,170: Methylene 11 3 Hydroxy-6- F luoro-I ,4,6-Pregnatriene-3,20-di0ne (1 6 04,1 7cz-Methylene-J1fi-Hya'roxy-6-Flu0ro 1,o-Bisdehydroprogeslerone) (XIX) Following the procedure of Example 81, but substituting 16a,l7a-methylene-6-fluoro-1,4,6-pregnatriene-3,20- dione (XX) (from Example 48) as starting material, yields crystalline 16oz, 17OL-I1'1fithYl6Il6-I 1 fi-hydroxy-G- fluoro-l,4,6-pregnatriene-3,20-dione (XIX).

Alternatively, 16a,17a-methylene-l lfl-hydroxy-G-fluoro- 4,6-pregnadiene-3,ZO-dione (XIX), prepared by the method of Example 93, can be l-dehydrogenated by the method of Example 48 to give 16a,17a-methylene-1 1B- hydroxy-6-fiuoro-l,4,6-pregnatriene-3,204lione (XIX).

Example 105. 16a,17a Methylene 11f3-Hydroxy-6- Chloro-l,4,6-Pregltatriene-3,20-Di0ne (16u,17oc-Metllylene 11 ,fi-Hydroxy-ti-Chloro 1,6-Bisdelzydropr0gesterone) (XIX) Following the procedure of Example 84, but substituting 16a,l7a-methylene-6-chloro-1,4,6-pregnatriene-3,20- dione (XX) (from Example 50) as starting material, yields light colored crystals of 16a,17a-methylene-llf3- hydroxy-6-chloro-1,4,6-pregnatriene-3,ZO-dione (XIX).

Alternatively, 16a,l7a methylene llfi-hydroxy 6- chloro-4,6-pregnadiene-3,20-dione (XIX), prepared by the method of Example 94, can be l-dehydrogenated by the method of Example 49 to give 16a,17a-methy1ene-11/3- hydroxy-6-chloro-1,4,6-pregnatriene-3,20-dione (XIX).

Example 106.16a,17a-Methylene 1,4,6-Pregnatriene- 3,11,20-Tri0ne (XIXa), 16 ]7oc-Methylene-6u-Methyl- 1,4,6-Pregnatriene-3,11,ZO-Trione (XIXa), 160:,17a- Methylene 6 Fluoro 1,4,6 pregnalrl'ene 3,11,20- Trione (XIXa), and 1604,]7a-Methylene-6-Chl0r0- 1,4,6-Pregnatriene3,11,20-Tri0ne (X IXa) Following the procedure of Example 60, but substituting as starting materials, 16a,17a-methylene-1lit-hydroxy- 1,4,6-pregnatriene-3,20-dione (XIX) (from Example 102), 16,17a methylene 11/3-hydroxy-6-methyl-1,4,6- pregnatriene-3,20-dione (XIX) (from Example 103), 160:,17a methylene 11p hydroxy-6-fioro-1,4,6-pregnatriene-3,20-dione (XIX) (from Example 104), l6ot,l7ocmethylene 11fi-hydroxy-6-chloro-4,6-pregnatriene-3,20- dione (XIX) (from Example 105), yields, respectively, light colored, crystalline 16a,Not-methylene-1,4,6-pregna- 33 triene-3,1 1,20-trione (XIXa 16a,17a-methylene-6- methyl-1,4,6-pregnatriene-3,11,20-trione (XIXa), 16 17a-methylene-6-fluoro '1,4,6-pregnatr-iene-3,11,20-trionc (XIXa), and 1611,17amethylene 6-chloro1,4,6-pregnatriene-3,11,20-trione (XIXa) Example 107. 161:,17a-Methylene-5-pregnene-3,Il,20- Trione 3,20-Bis(Ethylene Ketal) [16ot,17otMethylene- J1 Ketoprogesterone 3,20 -Bis(Ethylene Ket'al)] (XIX b) 1 e A mixture of 300 mg. of 16a,17a-methylene-4-pregnene- 3,11,20-trione (XIXa) (from Example 60), 5 'ml. of ethylene glycol, 50mg. of para-toluenesulfonic acid monohydrate and 100 ml. of 'benzene is placedin a reaction flask equipped with ar'eflux condenser and a water trap so arranged that the condensed vapors pass through the water trap before returning to the reaction flask. The mixture is heated to reflux and allow to reflux for about i 5 hours while at the same time being agitated. The

water of reaction formed is continuously removed by cothe water trap. Thebenzene solution is then washed with successive portions of a dilute sodium bicarbonate solution and water, and then dried. The residue remaining after evaporation of the solvent is crude 16a,17u-methylene-5-pregnene-3,11,20-trione 3,20-bis(ethylene ketal) (XIXb) which is recrrystallized from ethyl acetate to give the pure, light colored, crystalline product.

Example 108.-16u,1 7a-Methylene-6-Methyl-j-Pregnene- 3,11,20-Trine .3,20-Bis(Ethylene Ketal) [160a,] 7a- Methylene 6-Methyl -1 l-Ketoprogesterone 3,20-Bis- (Ethylene Ketal)] (XIXb) Following the procedure of Example 107, but substituting 16a, 17OL-I'l'lfillhYl6116-60t-1'II6lLhyl-4 PIBgIll16-3, 1 1,20-tri- 1 one (XIXa) (from Example 61-) as starting material, yields pure, crystalline. 16a,17a-methylenee6 methyl-- pregnene-3,11,20-trione 3,20-bis(ethylene ketal) (XIXb).

Example 1095-9160 7a-Methy lene-6-Fluoro-5-Pregnene- 3,11 ,20 -Tri0 ne -3,'20-Bis(Ethylene Ketal) [1602,1700- Methylene 6 Fluoro .l1 Ketoprogesterone 3,2 0-Bis- (Ethylene Ketal)] (XIXb) Following the procedure of Example 107, but substituting 16a,17beinethylene-6a-fiuoro-4-pregnene-3,11,20-trione (XIXa) (from Example 6 2) as starting material, yields crystalline 16a, 17 wmethylene-G-fluoro-S -pregnene-3,1 1,20-

trione 3,20-bis(ethylene ketal) (XIXb).-

Example 1l0. -16a,17a-Methylene-6-Flu0r0-5-Pregnene- 3,11,20-Triqne 3,20-Bis(Ethylene" Ketal) [160a,17ot- Methylene 6 Fluoro 1] Ket0pr0gester0ne 3,20-Bis- (Ethylene Ketal)] (XIXb) Following the procedure of Example 107, but substituting 16a,17ot-methylene-6B-fiuoro-4-pregnene-3,11,20-

" trione (XIXa) (from Example 63') as starting material, 1 yields crystalline '16a,17a-methylener6-fluoro-5-pregnene- 3,11,20-trione 3,20-bis(ethylene ketal) (XIXb) Example 111 .16 a,17a-Methylene-6-Chlor0-5-Pregnene- 3,11,20-Tri0ne 3,20-Bis(Ethylene Ketal) -[16a,17a-

Methylene 6 I1 Ketoprogesterone 3,20-Bis-(Ethylene Ketal)] (XIXb) Following the procedure of Example 107, but substituting 16a,17 -methylene-a-chloro 4-pregnene 3 ,11,20- trione (XIXa) (from Example 64) as starting material, yields pure, crystalline" '16oz,17ot-methylene-6 chloro-5- pregnene-S ,1 1,20-trione 3,'20"-bis(ethylene ketal) (XIXb) Example 112.16a,1 7a-Methylene-l Ip-HydrOxy-S-Pregnene-3,20-Dione 3,20-Bis (Ethylene Ketal) [16a,17 x- Methylene-1lp-Hydroxyprogesterone 3,20-Bis(Ethylene Ketal)] (XIXc) i To a solution of 10 g. of lithium aluminum hydride suspended in 800 ml. of ether is added 10 g. of 16a,17a-

methylene-5-pregnene 3,11,20 trione 3,20 bis(e'thy1ene distillation with the refluxing benzene and is collected in V Example 113.16a,17a-Methylene-6 Methyl 11 5 -Hydr0xy-5-Pregnene-3,20-Diane 3,20-Bis(Ethylene Ketal) [1 6 (1,1 7a-M ethylenefi-M ethyl-.1 1 p Hydroxyprogesterone 3,20-Bt's(Ethylene Ketal)] (XIXc) Following the procedure of Example 112 but substituting 16a,17a-methylene-6-rnethyl-5-pregnene-3,11,20- trione 3,20-bis(ethylene ketal) (XIXb) (from Example 108) as starting material, yields crystalline l6oc,l7otmethylene-6-methyl-llfl-hydroxy-5-pregnene-3,20 dione 3,20-bis(ethylene ketal) (XIXc). Example ]14.16a,17a-Methylene 6 Flnoro 11,8 Hydr0xy-5-Pregnene-3,20 Dione 3,20-Bis(Ethylene Ketal) [160a,] 7'a-Methylene-6-Flu0r0 11B Hydroxyprogesterone 3,20-Bis(Ethylene Ketal)] (XlXc) Following the procedure of Example 112, but substituting 16a,17a-methylene-6-fluoro-5-pregnene-3 ,1 1,20-trione 3,20 -bis(ethyleneketal) (XIXb) (from Example 109) as starting material, yields crystalline 16a,17a-methylene-6- fiuoro- 11,6-hydroxy-5-pregnene-3 ,20-dione 3 ,20-bis (ethylone ketal) (XIXa).

Examplr l15.-16a,1 flan-Methylene 6 Chloro 11,8 Hydr0xy-5-Pregnene-3,20-Dione 3,20-Bis(Ethylene Ketal) [160a,] 7u-Jl4ethylene-6-Chloro 1113 H ydroxyprogester- ;0ne:3,20-Bis(Ethylene Ketal)] (XIXc) Followingthe procedure of Example 112, but substitutin'g" 160;,17ot-methyIene-G-chloro-5-pregneue-3,11,20-trione -3 ,20-bis(ethylene ketal) (XIXb) (from Example 111) as startingmaterial, yields light colored, crystalline l6oc,17ocmethylenefi-chloro-llfi-hydroxy-S-pregnene 3,20 dione 3,20-biS-(ethylene ketal) (XIXc).

Example How-160e,] 7a-Methylene-l1fi H ydr0xy-4-Pregne'ne-3,20-Di0ne (1 6x170: Methylene 115 Hydroxy- I progesterone) (XIX) To a solution of 2 g. of 160:,l7oc-II16thYl6Il6-llfi-hydroxyprogesterone 3,20-bis(ethylene ketal) (XlXc) (from Example 112), in 75 ml. of acetone, is added one ml. of concentrated sulfuric acid in 25 ml. of water and the resulting acidic mixture allowed to stand for about 15 hours. The solution is then concentrated and water added until crystallization takes place. The thus obtained 16a,17otmethylene-1lfi-hydroxyprogesterone (XIX) is collected ona filter and purified by recrystallization from ethyl acetate to give pure l 6a,1 7a-methylene-1lfi-hydroxyprogesterone (XIX).

Example 117.-16a,17oz-Methylene-6a-Methyl 11,3 Hydr0xy-4-Pregnene-3,20 Di0ne (1611,] 7a M ethylene-6a- M ethy H .1 5-H ydroxy progesterone) (XIX) Following the procedure of Example 116, but substituting 16a,l7a-rnethylene-6-methyl-1lfi-hydroxy-S-pregnene- 3,20-dione 3,20-bis(ethylene ketal) (XlXc) (from Example 113) as start-ing material, yields crystalline 16a,17 amethylene-6aamethyl l1B-hydroxy-4-pregnene-3,20 dione (XIX).

Example ll.8.16a,17a-Methylene-6a Fluoro 11,6 Hydr0xy-4-Pregnene-3,20-Di0ne (1 60;,1 7a M ethylene-6a- Fluoro-llp-Hydroxyprogesterone) (XIX) Following the procedure of Example 116, but substituting ,16oz,l7 0t-TI16tl1Yl6116-6-fl11010-1 1 fl-hydroxy-S-pregnene- 35 3,20-dione 3,20-bis(ethylene ketal) (XIXc) (from Example 114) as starting material, yields crystalline 1600,170tmethylene-60t fluoro-llfl hydroxy 4 pregnene 3,20- dione (XIX).

Example 119.160t,170t-Methylene-6a-chloro 11,3 Hydroxy-4-Pregnene-3,20-Di0ne (1-60t,170t M ethylene-600- Chloro-JJfl-Hydroxyprogesterone) (XIX) Following the procedure of Example 116, but substituting 16a,17ot-IIl6thYl61'16-6-Chl0lO-l 1B-hydroxy-5-pregnene- 3,20-dione 3,20-bis(ethylene ketal) (XIX) (from Example 115) as starting material, yields light, crystalline 1600,170tmethylene-600-chloro-11p-hydroxy-4-pregnene-3,20 dione (XIX).

Example 120.-160t,1700 Methylene 90 Fluoro 11B- Hydroxy 4 Pregnene 3,20 Dione (160,170t- Methylene 900 Fluora 11 3 Hydroxyprogesterone) (XXV) (a) A mixture of 1 g. of 16a,1700-methylene-1lfi-hydroxy-4-pregnene-3,20-dione (XIX) (from Example 116), 650 mg. of N-bromoacet-amide and 6 ml. of pyridine is stirred in the dark for a period of about 30 minutes. The mixture is cooled in an ice-water bath and a stream of sulfur dioxide is directed onto the surface of the stirred mixture until a negative potassium iodide-starch test is obtained. Fifty ml. of water is then added to the mixture and the mixture maintained at about 5 C. -for about 30 minutes. The precipitated white solid is filtered, washed with water and dried under vacuum. After crystallization from acetone there is obtained crystalline 1600,1700 methylene 4,9(11) pregnadiene 3,20 dione (XXII).

(b) 0.5 gram of 1600,17a-methylene-4,9(11)-pregnadiene-3,20-dione (XXII) is dissolved in 20 ml. of methylene chloride and thereto is added a solution of 1 ml. of 71% perchloric acid in ml. of water and 200 mg. of N-bromoacetamide in 50 ml. of tertiary butyl alcohol. The solution is maintained at room temperature for about fifteen minutes and then mixed with a solution of 0.3 of sodium sulfite in 12 ml. of water. The mixture is distilled at reduced pressure until the residual solution becomes cloudy. The product is then precipitated by the addition of 100 ml. of a mixture of ice-water. The white crystalline precipitate is filtered, washed with water, and then dried to give crystalline 1600,170t-methylene-90t-bromo- 1 1B-hydroxy-4-pregnene-3,20-dione (XXIII) (c) A mixture of 0.45 g. of 16a,170t-methylene-900 bromo 11B hydroxy 4 pregnene 3,20 dione (XXIII), 0.45 g. of anhydrous potassium acetate and 20 ml. of acetone is heated at its refluxing temperature for a period of 5 hours. The mixture is then cooled and poured into water and extracted with methylene chloride. The methylene chloride extract is dried and poured over a column of 25 grams of Florisil. The column is developed with Skellysolve B containing increasing proportions of acetone. The Skellysolve B plus 10% acetone eluate contains l60t,1700 methylene 95,115 oxido 4 pregnene- 3,20-dione (XXIV).

(d) A solution of 1 g. of 1600,1700-methylene-9 3,11,B- oxido-4-preguene-3,20-dione (XXIV) is dissolved in 50 ml. of methylene chloride and thereto is added 5 ml. of 48% hydrofluoric acid. The mixture is stirred vigorously for about 6 hours and then poured into an excms of cold aqueous 5% sodium bicarbonate solution. The methylene chloride layer is separated, dried with anhydrous sodium sulfate and then poured over a column of 100 of Florisil. The column is developed with Skellysolve B and acetone, the fractions containing 10% acetone are evaporated to dryness and recrystallized from acetone and Skellysolve B to give pure crystalline 16a, 1700 methylene 9a fluoro llfi hydroxy 4 pregnene-3,20-dione (XXV).

36 Example 121.--I6a,1700 Methylene 9a Flnoro 60L- Methyl 11,9 Hydroxy 4 Pregnene 3,20 Dione (160t,1700 Methylene 900 Flaoro 6a Methyl 11B- Hydroxyprogesterone) (XXV) Following the procedure of Example 120, but substituting 160:,1700 methylene 60 methyl 11p hydroxy- 4-pregnene-3,20-dione (XIX) (from Example 117) as starting material, yields crystals of 1606,170L-1T1BthYl61'16-90L- fiuoro 600 methyl 11 3 hydroxy 4 pregnene 3,20- dione (XXV).

Example 122.160t,1700 Methylene 60t,900 Diflaoro- 11,8 Hydroxy 4 Pregnene 3,20 Dione (1600,1700 Methylene 600,900 Difla0r0-11p Hydroxyprogesterone) (XXV) Following the procedure of Example 120, but substituting 1600,1700 methylene 6C1. fluoro 115 hydroxy- 4-pregnene-3,20-dione (XIX) (from Example 118) as starting material, yields crystalline l60t,l70t-methylene 600,900 difluoro 11p hydroxy 4 pregnene 3,20 dione (XXV).

Example 123.-160c,170t Methylene 900 Fluoro 66t- Chloro 11B Hydroxy 4 Pregnene 3,20 Dione (1600,170: Methylene 9a -Fla0r0 600 Chloro 11B- Hydroxyprogesterone) (XXV) Following the procedure of Example 120, but substituting 160t,170t methylene 600 chloro a 116 hydroxy 4- pregnene-3,20-dione (XIX) (from Example 119) as start ing material, yields light colored, crystalline 160a1700- methylene 900 fluoro 600 chloro 11,8 hydroxy 4* pregnene-3,20-dione (XXV).

Example 124.-160L,170t Methylene 900 Fluoro 11B- Hydroxy 4,6 Pre'gnaaiene 3,20 Dione (XXV), 1600,1700 Methylene a Fluoro 6 Methyl Hydroxy 4,6 Pregnadiene 3,20 a Dione (XXV), 1600,1700 Methylene 6,90t Difluoro 11,8 Hydroxy- 4,6 Pregnadiene 3,20 Dione (XXV),- and 16a,1700- Methylene 90: FluorO 6 Chlo'ro 11f Hydroxy= 4,6-Pregnadiene-3,20-Di0ne (XXV) Following the procedure of Example 120, but substituting as starting materials, 16a,170t-methylene-l lfl-hydroxy- 4,6 pregnadiene 3,20 dione (XIX) (from Example 91), t,170t methylene 6 methyl llfl hydroxy- 4,6-pregnadiene3,20-dione (XIX) (from Example 92), 1600,1700 methylene 6 fiuoro llfl hydroxy 4,6- pregnadiene-3,20dione (XIX) (from Example 93), and 1600,1700 methylene 6 chloro 116 hydroxy 4,6- pregnadiene-3,20-dione (XIX) (from Example 94) yields, respectively, light colored, crystalline 16a,170t-methylene- 9a fluoro 11,3 hydroxy 4,6 pregnadiene 3,20 dione (XXV), 160,170t-methylene-9a-fiuoro-6-methyl-1 1,8- hydroxy-4,6-pregnadiene-3,20-dione (XXV), 160t,1700- methylene 6,90t difluoro 11B hydroxy 4,6 pregnadiene 3,20 dione (XXV) and 160t,170t methylene- 90; -fluoro 6 chloro 1113 hydroxy 4,6 pregnadiene- 3,20-dione (XXV).

Example 125.-160t,170t Methylene 90 Fluoro 11B- Hydroxy 1,4 Pregnadiene 3,20 Dione (XXV), 1600,170: Methylene 900 Fluoro 6a Methyl 11p- Hydroxy 1,4 Pregnadiene 3,20 Dione (XXV), 160,170: Methylene 60t,900 Dt'flaoro 1118 Hydroxy 1,4 Pregnadiene 3,20 Dione (XXV), 16a, 1700 Methylene 613,90: Diflaoro 11,8 Hydrvxy- 1,4 Pregnadt'ene 3,20 Di ne (XXV) and 1600,1700- Methylene 900 Fluoro 600 -Chl0r0 11,8 Hydroxy- 1,4-Pregnadiene-3,20-Dione (XXV) Following the procedure of Example 120, but substituting as starting materials, 160$,170t-H16thYl6l'16-1lfi-hydlOxy- 1,4 pregnadiene 3,20 dione (XIX) (from Example 96), 1611,1700 methylene 6a methyl 11p hydroxy- 1,4 pregnadiene 3,20 dione (XIX) (from Example 97), 160:,170; methylene 60 fluoro: l-lfi hydroxy-' 1,4-pregnadiene-3,20 dione (XIX) (from Example 98), 1611,1704 methylene 65 fluoro 11B hydroxy 1,4- p i (XI tfrqmiEx mpl and 16a,17a methylene 6a chloro 11p hydroxy 1,4- pregnadiene-3,20 dione I (XIX) (from Example 100) yields, respectively, light colored, crystalline 16a,17a-

methylene 9oc-flll010 11B hydroxy 1,4 pregnadiene- 3,20 dione (XXV), 16a,17a methylene 9a fluoro- 6oz methyl 11/3 hydroxy -'1,4 pregnadiene 3,20- dione (XXV), 16a,17tat-methylene-6a-,9adifluoro-1lfl-hydroxy 1,4 -pregnadiene 3,20 dione (XXV), 17a methylene 6 8,90 difluoro 11E hydroxy 1,4- pregnadiene-3,20-dione (XXV) and 16u,17a-methylene- 90c fluoro 6oz chlor-o 11/3 hydroxy 1,4 pregnadiene-3,20-dione (XXV).

Following the procedure of Example 120, but substitut- 1,4,-6-pregnatriene-3,20-dione (XIX) "(from ',,Example 102), 16a,17oc methylene- 6-methyl-11fl-hydroxy-1,4',6- pregnatriene-3,20-dione (XIX) (from Example 103), 161x, 1704 methylene 6 fluoro-l-lfi-hydroxy-1,4,6-pregnatriene-3,20-dione (XIX) (from Example 104) and 16a,17amethylene 6,-chloro-1lfi-hydroxy-l,4,6-pregnatriene-3,20- dione (XIX) (from Example 105) yields, respectively, light color, crystalline 16a,'17a-methylene-9u-fluoro-l1B- hydroxy-1,4,6-pregnatriene-3,20-dione (XXV), 160:,1711- methylene 9a-fluoro-6-methyl-1lfl-hydroxy-l,4,-6-pregnatriene-3,20-dione (XXV), 16a,17ot-methylene-6,'9u-difluoro-1 1fi-hydroxy-1,4,6-pregnatriene-3,ZQ-dione (XXV) and 16ot,17u methylene 9oz fluoro-6-chloro-l,4,6-pregnatriene-3,2:0-dione (XXV).

, Example 127.16,u,1 7a 7 M ethylene- 90c Flu0ro-4-Preg- Example 120) in 4 ml. of acetic acid is added 60 mg. of chromic anhydride,.dissolved in 1 ml. of acetic acid and 0.1 m1. of water. The mixture is allowed to stand at room temperature for a period of, about 4 hours, then poured and extracted with three m1.,portions of methylene chloride. The methylene chloride extracts are combined, washed with water, dried over anhydrous sodium sulfate,

evaporated, and the thus produced residue twice recrystallized from methanol to give 16a,17a-methylene-9wfiuoro 4-pregnene-3 ,11,20-trione (XXVI) 4"- Pregame-3,11,ZO-Tribrte (16a,1 7a Methyler te'-9a- Fluaro-6a -Metlzyl-1J Ket oprogesteroae) (XX VI Following the procedure of Example 127, but; substituting 1'6a,17a-methylene=9a-fiuoro-6a-methyl-1lj8-hydroxy- 4-pregnene-3,20 dione :(XXV) (from Example 1121) as starting material, yields crystalline 16u,17a-methylene-9a fluoro-6u-methyl-4pregnene-3, 1 1,20-trione (XXVI) Example 129. ,I6a,1 7a M ethylene-6a,9a-Difluoro-4- Pregnene 3,11,20} Trione I (1600,] 7 a-M ethylene-.6 cc,9u- Difluoro-l 1 -Ketopro gesterone) (XXVI) Following the procedure of Example 127, but substitut ing 16a,17a-methylene-6oa9a-difluoro-11B-hydroxy-4-pregnene-3,20-dione (XXV) (from Example 122) as starting material, yields crystalline '16a,17a-methylene 6a,=9a-difiuoro-4-pregnene-3, 1 1,20 -tri0ne (XXVI) Example 130,16a,17a-Methylene-9 -Flu0r0-6u -Chl0r 0- 4 Pregnene 3,11,20-Tri0ne (1611,] 7a-Methylen'e-9u- Flu 0rfa-6a-Chl 0r0-1I-Ketoprogesterone) (XXVI) Following the procedure of Example 127, but substituting 16a,17a-methylene-9a-fluoro-6a-chloro-1lp-hydroxy- 4-pregnene-3,20-dione (XXV) (from Example 123) as starting material, yields light colored, crystalline 16a-17amethylene 9a.- fluoro fia-chloroA-pregnene-3,11,2'0-trione (XXVI).

Example 131. 16u,17a-Methylene-9a-Flu0r0-4,d-Pregnadiene-3,1 1,20-Tri0ne (XXVI), 1 6 11,1 7ix-M ethylene- 9m Fluoro 6-Methyl-4;6=Pregnadiene 3,1J ,ZO-Trione (XXVI), 160a,] 7a-Mezhylene-6,9u-Diflu0ro-4,6-Pregnadiene-3,11,20-Tri0ne (XXVI) and 16a,17a-Methylene- 90c Fluoro 6 Chl0r0-4,6-Pregnadiene-3,11,20-Tri0ne (X X VI Following the procedure of Example 127 but substituting as starting materials 16a,17a-methylene 9a-fluoro-11,8- hydroxy 4,6-pregnadiene-3,20-dione (XXV) (from Example 124), 16a,17a-methylene-9a fluoro-6-rnethyl-l1/3- hydroxy-4, 6-pregnadiene-3,20-dione (XXV) (from Example 124), 1604,17u methylene-6,9a-difluoro-1lB-hydroxy-4,6-pregnadiene-3,20-dione (XXV) (from Example 124) and 16a,17u-methylene-9a-fluoro-6-chloro-1lfi-hydroxy- 4,6-pregnadiene-3,20-dione (XXV) (from Example 124) yields, respectively, light colored, crystalline 16w 17a methylene 9a-fiuoro-4,6-pregnadiene-3,11,20-trione nadiene-3,11,20-trione (XXV), 16a,l7a-methylene-9afluoro 6,90: difluoro 4, 6 -pregnadiene 3,11,20-trione pregnadiene-3,11,20-tri0ne (XXVI).

into 5-0 ml. of water, neutralized with sodium bicarbonate" droxy-l,4-pregnadiene-3,20-dione (XXV) (from Exam- 11,4 pregnadiene-3,20=dione (XXV) (from Example 125) ,1,4-pregnadiene-3,20-dione (XXV) (from Example 125) yields, "respectively," light colored, crystalline- 16a,17amethylene c fluoro 1,4 pregnadiene-3,11,20trione (XXVI), :,17a methylene- 96tfluoro6u-methyl-1,4- pregnadiene-3,11,2'0 trione (XXVI), 1-6a,17a-methylene- 600,90: difiuoro-1,4-pregnadiene-3,11,20-trione (XXVI), l'6oc,17oc methylene 6fl,9oa-difluoro-1,4-pregnadiene-3,11, '20-tri0ne (XXVI) and 16a,17a-methyIeneQa-fluOrQ-Gachloro-l,4-pregnadiene-3,1 1,20-trione (XXVI).

Example 133 .1 6 0a,] 7a-Methylene-9a-Fluoro-l ,4,6-Pregnatriene-3,11,20-Tri0ne (XXVI), 160a,] flan-Methylene- 9a Fla0r0-6-Melhyl-I,4,6-Pregnatriene3,11,20-Tri0ne '(XXVI) 160a,] 7oc-Methyle ne-6,9a-Difluoro-I ,4,6Pregnatriene-3,1 1,20-Tri0ne (XXVI) and 16a,I7u-Methylene 9a F luoro 6-Chlor0-1,4,6-Pregnatriene-3,11,20- Trione (XXVI) Following the procedure of Example 127, but substitutas l starting materials 16a,1 7a-methylene-9a-fluoro- 1lj3-hydroxy 1,4,6-pregnatriene-3,20 dione (XXV) (from "Example 126), l6a,17wmethylene-9a-fluoro-6-methyll-lfi-hydroxy-l,4,6-pregnatriene-3,20-dione (XXV) (from Example 126), 16a,17a methylene-9u-fiuoro-6,9a-difluo- CH5 CH5 Ii -CH.

wherein R is selected from the group consisting of methyl, fluorine and chlorine.

2. 16oc,17oc methylene 6a methyl-4-pregnene-3,20- dione.

3. 16a,17m-methylene-6a-fiuoro-4-pregnene-3,ZO-dione. 4. 16m,17u-methylene-6a-ehloro-4-pregnene-3,20-dione. 5. Compounds of the formula wherein R is selected from the group consisting of methyl, fluorine and chlorine.

6. 16a,17a-methylene 60c methyl-1,4-pregnadiene-3, 20-dione.

7. 160:,17u methylene-6a-fluoro-1,4-pregnadiene3,20- dione.

8. 160:,17a. methylene6a-ch1oro-1,4-pregnadiene-3,20- dione.

9. Compounds of the formula CH: Innwherein R is selected from the group consisting of methyl, fluorine and chlorine.

10. 16a,17a-methylene-6-methy1 4,6 pregnadiene-3, 20-dione.

11. 160:,1711 methylene-6-fluoro-4,6-pregnadiene-3,20 dione.

'40 12. 16a,17a methylene-6-chloro-4,6-pregnadiene-3,20- dione.

13. Compounds of the formula wherein R is selected from the group consisting of methyl, fluorine and chlorine.

14. 16a,17a methylene-6-methyl-1,4,6-pregnatriene-3, ZO-dione.

15. 16a,17a-methy1ene-6-fluoro 1,4,6 pregnatriene-3, 20-dione.

16. :,l7a methylene-6-chloro-1,4,6-pregnatriene-3, ZO-dione.

17. A process for the production of a compound of the formula CH; (i=0 j "CH:

wherein R is selected from the group consisting of hydro- .gen, methyl, fluorine and chlorine, which comprises reacting a compound of the formula wherein R has the same meaning as above, with a strong acid.

18. A process for the production of a compound of the formula 

1. A COMPOUNDS OF THE FORMULA 